id
stringlengths 8
11
| title
stringlengths 14
124
| content
stringlengths 0
34k
| contents
stringlengths 20
34k
| nordid
int64 0
1.32k
| rare-disease
stringlengths 4
103
|
|---|---|---|---|---|---|
nord_771_3
|
Affects of Measles
|
Measles affects males and females equally and occurs worldwide. As a result of vaccination to prevent measles, all cases that now occur in the United States have been brought from other countries. Measles continues to be a significant public health problem in developing countries, with 30-40 million cases per year. Most reported cases are from Africa.
|
Affects of Measles. Measles affects males and females equally and occurs worldwide. As a result of vaccination to prevent measles, all cases that now occur in the United States have been brought from other countries. Measles continues to be a significant public health problem in developing countries, with 30-40 million cases per year. Most reported cases are from Africa.
| 771 |
Measles
|
nord_771_4
|
Related disorders of Measles
|
Rubella, or three-day measles, is marked by mild constitutional symptoms that may result in abortion, stillbirth, or congenital defects in infants born to mothers infected during the early months of pregnancy. Other symptoms may include a two to three week incubation period with no recognizable symptoms, mild course of short duration, low fever, rash (less extensive than other types of measles), a reddish flush simulating that of scarlet fever which may be noticed on the face, enlargement of lymph nodes, and a normal blood count.Symptoms are usually mild in children with rubella. Adults characteristically experience fever, discomfort, headache, weakness or exhaustion, stiff joints, and mild nasal membrane inflammation (rhinitis). Encephalitis is a rare complication that has occurred during extensive outbreaks of rubella among young adults in the armed services. Transient testicular pain is also a frequent complaint in affected adult males. (For more information on rubella, choose “rubella” as your search term in the Rare Disease Database.)Scarlet fever is an infection caused by bacteria that usually affects the mouth/throat area (pharynx), but may also affect the skin or birth canal. Patients may experience headache, abdominal pain, nausea, and a skin rash. Rarely, complications are lymphocytic meningitis and hepatitis. A reddish flush may be apparent on the face, chest and extremities, with tiny red spots in some cases. The disease is much milder now than in the past, and complications are rare when properly treated.Roseola infantum (exanthem subitum or pseudorubella) is an acute disease of infants or very young children characterized by high fever, absence of localizing symptoms or signs, and appearance of red spots (a rubelliform eruption) simultaneously with, or following, lowering of the fever (defervescence). The cause and mode of transmission are not known, but the disease is probably communicable and caused by a neurodermotropic virus. It occurs most often in the spring and fall. Minor local epidemics have been reported.Atypical measles syndrome (AMS) is most common in adolescents and young adults and usually associated with prior immunization using the original killed measles vaccines, which are no longer in use. However, live measles vaccine administration has also been known to precede development of AMS, perhaps as a result of inadvertent inactivation due to improper storage. Presumably, inactivated measles virus vaccines do not prevent wild virus infection and can sensitize patients so that disease expression is altered significantly. AMS may begin abruptly, with high fever, toxicity, headache, abdominal pain, and cough. The rash may appear one to two days later, often beginning on the extremities. Swelling (edema) of the hands and feet may occur, pneumonia is not uncommon, and nodular densities in the lungs may persist for three months or longer.
|
Related disorders of Measles. Rubella, or three-day measles, is marked by mild constitutional symptoms that may result in abortion, stillbirth, or congenital defects in infants born to mothers infected during the early months of pregnancy. Other symptoms may include a two to three week incubation period with no recognizable symptoms, mild course of short duration, low fever, rash (less extensive than other types of measles), a reddish flush simulating that of scarlet fever which may be noticed on the face, enlargement of lymph nodes, and a normal blood count.Symptoms are usually mild in children with rubella. Adults characteristically experience fever, discomfort, headache, weakness or exhaustion, stiff joints, and mild nasal membrane inflammation (rhinitis). Encephalitis is a rare complication that has occurred during extensive outbreaks of rubella among young adults in the armed services. Transient testicular pain is also a frequent complaint in affected adult males. (For more information on rubella, choose “rubella” as your search term in the Rare Disease Database.)Scarlet fever is an infection caused by bacteria that usually affects the mouth/throat area (pharynx), but may also affect the skin or birth canal. Patients may experience headache, abdominal pain, nausea, and a skin rash. Rarely, complications are lymphocytic meningitis and hepatitis. A reddish flush may be apparent on the face, chest and extremities, with tiny red spots in some cases. The disease is much milder now than in the past, and complications are rare when properly treated.Roseola infantum (exanthem subitum or pseudorubella) is an acute disease of infants or very young children characterized by high fever, absence of localizing symptoms or signs, and appearance of red spots (a rubelliform eruption) simultaneously with, or following, lowering of the fever (defervescence). The cause and mode of transmission are not known, but the disease is probably communicable and caused by a neurodermotropic virus. It occurs most often in the spring and fall. Minor local epidemics have been reported.Atypical measles syndrome (AMS) is most common in adolescents and young adults and usually associated with prior immunization using the original killed measles vaccines, which are no longer in use. However, live measles vaccine administration has also been known to precede development of AMS, perhaps as a result of inadvertent inactivation due to improper storage. Presumably, inactivated measles virus vaccines do not prevent wild virus infection and can sensitize patients so that disease expression is altered significantly. AMS may begin abruptly, with high fever, toxicity, headache, abdominal pain, and cough. The rash may appear one to two days later, often beginning on the extremities. Swelling (edema) of the hands and feet may occur, pneumonia is not uncommon, and nodular densities in the lungs may persist for three months or longer.
| 771 |
Measles
|
nord_771_5
|
Diagnosis of Measles
|
Measles is diagnosed by physical findings. This disease is characterized by fever, cough, acute nasal mucous membrane discharge (coryza), inflammation of the lining of the eyelids (conjunctivitis), a spreading rash, and eruption of small, irregular, bright red spots (Koplik's spots) on the inner cheeks in the mouth with a minute bluish or white speck in the center of each. Confirmation of measles virus infection can be done with a blood test called a measles virus sandwich-capture immunoglobulin (IgM) antibody assay. This test is most accurate if performed after the third day of rash up to one month after the beginning of rash.
|
Diagnosis of Measles. Measles is diagnosed by physical findings. This disease is characterized by fever, cough, acute nasal mucous membrane discharge (coryza), inflammation of the lining of the eyelids (conjunctivitis), a spreading rash, and eruption of small, irregular, bright red spots (Koplik's spots) on the inner cheeks in the mouth with a minute bluish or white speck in the center of each. Confirmation of measles virus infection can be done with a blood test called a measles virus sandwich-capture immunoglobulin (IgM) antibody assay. This test is most accurate if performed after the third day of rash up to one month after the beginning of rash.
| 771 |
Measles
|
nord_771_6
|
Therapies of Measles
|
TreatmentThere is no specific treatment for measles. Vitamin A is recommended for some infected children. Symptoms can be treated with bed rest, Tylenol (acetaminophen) and humidified air. The use of aspirin to treat viral diseases in children and young adults should be avoided because of the risk of Reye syndrome, a rare but life-threatening condition. (For more information on this disorder, choose "Reye" as your search term in the Rare Disease Database.)Vaccination for measles is the most effective method to prevent outbreaks of measles. The vaccine approved in 1963 is no longer in use. Anyone who received vaccine between 1962 and 1969 should be re-immunized with the current vaccine. The current live vaccine is strong enough to produce immunity to measles, but not so strong as to produce severe reactions. Vaccine failure occurs in 5% of cases.The American Academy of Pediatrics recommends that an initial immunization of measles, mumps, and rubella (MMR) be given at fifteen months of age and a second MMR immunization be given at the beginning of middle school or junior high school. Students entering high school and college should have their immunization records reviewed to be sure that they have received both doses of vaccine.
|
Therapies of Measles. TreatmentThere is no specific treatment for measles. Vitamin A is recommended for some infected children. Symptoms can be treated with bed rest, Tylenol (acetaminophen) and humidified air. The use of aspirin to treat viral diseases in children and young adults should be avoided because of the risk of Reye syndrome, a rare but life-threatening condition. (For more information on this disorder, choose "Reye" as your search term in the Rare Disease Database.)Vaccination for measles is the most effective method to prevent outbreaks of measles. The vaccine approved in 1963 is no longer in use. Anyone who received vaccine between 1962 and 1969 should be re-immunized with the current vaccine. The current live vaccine is strong enough to produce immunity to measles, but not so strong as to produce severe reactions. Vaccine failure occurs in 5% of cases.The American Academy of Pediatrics recommends that an initial immunization of measles, mumps, and rubella (MMR) be given at fifteen months of age and a second MMR immunization be given at the beginning of middle school or junior high school. Students entering high school and college should have their immunization records reviewed to be sure that they have received both doses of vaccine.
| 771 |
Measles
|
nord_772_0
|
Overview of Meckel Syndrome
|
Summary Meckel syndrome is a rare inherited disorder characterized by abnormalities affecting several organ systems of the body. Three classic symptoms are normally associated with Meckel syndrome: protrusion of a portion of the brain and its surrounding membranes (meninges) through a defect in the back of the skull (occipital encephalocele), multiple cysts on the kidneys (cystic kidneys), and extra fingers and/or toes (polydactyly). Affected children or fetuses may also have abnormalities affecting the head and face (craniofacial area), liver, lungs, heart, and genitourinary tract. The lack of amniotic fluid surrounding the fetus (oligohydramnios) induces incomplete development of the lungs (pulmonary hypoplasia).Because of these serious health problems, infants born with Meckel syndrome do not survive longer than a few days or weeks. Most affected infants die of kidney failure or respiratory problems. Parents sometimes choose to terminate a pregnancy when a fetus with Meckle syndrome is diagnosed during pregnancy.Meckel syndrome is inherited as an autosomal recessive condition through thirteen genes: B9D1, B9D2, CC2D2A, CEP290, MKS1, RPGRIP1L, TCTN2, TCTN3, TMEM67, TMEM107, TMEM216, TMEM231 and TMEM237.Introduction The first report of Meckel syndrome was published by Johann Friedrich Meckel in 1822. In 1934, G.B. Gruber published reports on individuals with Meckel syndrome and named the disorder dysencephalia splanchnocystica.
|
Overview of Meckel Syndrome. Summary Meckel syndrome is a rare inherited disorder characterized by abnormalities affecting several organ systems of the body. Three classic symptoms are normally associated with Meckel syndrome: protrusion of a portion of the brain and its surrounding membranes (meninges) through a defect in the back of the skull (occipital encephalocele), multiple cysts on the kidneys (cystic kidneys), and extra fingers and/or toes (polydactyly). Affected children or fetuses may also have abnormalities affecting the head and face (craniofacial area), liver, lungs, heart, and genitourinary tract. The lack of amniotic fluid surrounding the fetus (oligohydramnios) induces incomplete development of the lungs (pulmonary hypoplasia).Because of these serious health problems, infants born with Meckel syndrome do not survive longer than a few days or weeks. Most affected infants die of kidney failure or respiratory problems. Parents sometimes choose to terminate a pregnancy when a fetus with Meckle syndrome is diagnosed during pregnancy.Meckel syndrome is inherited as an autosomal recessive condition through thirteen genes: B9D1, B9D2, CC2D2A, CEP290, MKS1, RPGRIP1L, TCTN2, TCTN3, TMEM67, TMEM107, TMEM216, TMEM231 and TMEM237.Introduction The first report of Meckel syndrome was published by Johann Friedrich Meckel in 1822. In 1934, G.B. Gruber published reports on individuals with Meckel syndrome and named the disorder dysencephalia splanchnocystica.
| 772 |
Meckel Syndrome
|
nord_772_1
|
Symptoms of Meckel Syndrome
|
The specific symptoms associated with Meckel syndrome vary greatly from one individual to another. Affected children will not have all of the symptoms detailed below. Central nervous system, pulmonary or kidney abnormalities always result in perinatal death.The most common central nervous system abnormality associated with Meckel syndrome is occipital encephalocele, a condition in which an infant is born with a gap in the skull (i.e., a part of one or more of the plates that form the skull does not seal). The membranes that cover the brain (meninges) and brain tissue often protrude through this gap. Occipital encephalocele may result in accumulation of excessive cerebrospinal fluid (CSF) in the skull, which causes pressure on the tissues of the brain (hydrocephaly). Additional central nervous system abnormalities that may occur in infants with Meckel syndrome include the absence of a major portion of the brain, skull, and scalp (anencephaly), absence of the median part of the posterior brain (cerebellar vermis agenesisi), and a condition known as microcephaly, in which the head circumference is smaller than would be expected for age and sex. Affected infants may have distinctive facial features including an abnormally small jaw (micrognathia); enlarged, low-set and malformed ears; cleft palate; cleft lip; sloping forehead; and short neck. Affected children may have eye (ocular) abnormalities including abnormally small eyes (microphthalmia), and underdevelopment of the nerves of the eyes (optic nerve hypoplasia or coloboma). Multiple cysts on the kidneys (multicystic kidney dysplasia) are the most common symptom associated with Meckel syndrome. The condition is characterized by normal kidney tissue that is replaced by fluid-filled sacs or cysts of varying sizes that become larger (10-20 times greater than normal) as the disease progresses. Findings associated with cystic kidneys include loss of kidney function, leading to end-stage renal failure. Improper kidney function also results in a reduction in the amount of amniotic fluid surrounding the developing fetus (oligohydramnios).Affected individuals may also have extra fingers and toes, most often extra fingers on the “pinky” side of the hands (postaxial polydactyly). Additional skeletal malformations include bowing of the long bones of the arms and legs, curvature of the fifth fingers (clinodactyly), webbing of the fingers and toes (syndactyly), and club foot where the foot are rotated internally (talipes equinovarus).In some individuals, abnormalities of the genitourinary tract may be present including failure of the one or both testes to descend into the scrotum (cryptorchidism), underdeveloped (hypoplastic) bladder, and incomplete development of genitalia.Some affected infants may have abnormalities affecting other organs of the body including the liver, lungs or heart. The liver can show excessive fibrous tissue (fibrosis) and widening (dilatation) and excessive number (proliferation) of the small passages that carry bile from the liver to the small intestines (bile ducts). The lungs may be underdeveloped (hypoplastic) and the structure that covers the entrance of the larynx when swallowing may be clefted (cleft epiglottis). The spleen may be missing (asplenia), or be present as multiple small spleens, rather than a single (polyspenia).Heart abnormalities may include atrial and ventricular septal defects (ASDs and VSDs) and patent ductus arteriosus or other more complex malformations. ASDs are characterized by an abnormal opening in the fibrous partition (septum) that separates the two upper chambers (atria) of the heart. VSDs are characterized by an abnormal opening in the septum that divides the heart’s two lower chambers (ventricles). The size, location, and nature of a septal defect and any associated abnormalities determine the severity of symptoms. Patent ductus arteriosus is a condition in which the passage (ductus) between the blood vessel that leads to the lungs (pulmonary artery) and the major artery of the body (aorta) fails to close after birth.Genital abnormalities include external or internal genitalia in both male or female.
|
Symptoms of Meckel Syndrome. The specific symptoms associated with Meckel syndrome vary greatly from one individual to another. Affected children will not have all of the symptoms detailed below. Central nervous system, pulmonary or kidney abnormalities always result in perinatal death.The most common central nervous system abnormality associated with Meckel syndrome is occipital encephalocele, a condition in which an infant is born with a gap in the skull (i.e., a part of one or more of the plates that form the skull does not seal). The membranes that cover the brain (meninges) and brain tissue often protrude through this gap. Occipital encephalocele may result in accumulation of excessive cerebrospinal fluid (CSF) in the skull, which causes pressure on the tissues of the brain (hydrocephaly). Additional central nervous system abnormalities that may occur in infants with Meckel syndrome include the absence of a major portion of the brain, skull, and scalp (anencephaly), absence of the median part of the posterior brain (cerebellar vermis agenesisi), and a condition known as microcephaly, in which the head circumference is smaller than would be expected for age and sex. Affected infants may have distinctive facial features including an abnormally small jaw (micrognathia); enlarged, low-set and malformed ears; cleft palate; cleft lip; sloping forehead; and short neck. Affected children may have eye (ocular) abnormalities including abnormally small eyes (microphthalmia), and underdevelopment of the nerves of the eyes (optic nerve hypoplasia or coloboma). Multiple cysts on the kidneys (multicystic kidney dysplasia) are the most common symptom associated with Meckel syndrome. The condition is characterized by normal kidney tissue that is replaced by fluid-filled sacs or cysts of varying sizes that become larger (10-20 times greater than normal) as the disease progresses. Findings associated with cystic kidneys include loss of kidney function, leading to end-stage renal failure. Improper kidney function also results in a reduction in the amount of amniotic fluid surrounding the developing fetus (oligohydramnios).Affected individuals may also have extra fingers and toes, most often extra fingers on the “pinky” side of the hands (postaxial polydactyly). Additional skeletal malformations include bowing of the long bones of the arms and legs, curvature of the fifth fingers (clinodactyly), webbing of the fingers and toes (syndactyly), and club foot where the foot are rotated internally (talipes equinovarus).In some individuals, abnormalities of the genitourinary tract may be present including failure of the one or both testes to descend into the scrotum (cryptorchidism), underdeveloped (hypoplastic) bladder, and incomplete development of genitalia.Some affected infants may have abnormalities affecting other organs of the body including the liver, lungs or heart. The liver can show excessive fibrous tissue (fibrosis) and widening (dilatation) and excessive number (proliferation) of the small passages that carry bile from the liver to the small intestines (bile ducts). The lungs may be underdeveloped (hypoplastic) and the structure that covers the entrance of the larynx when swallowing may be clefted (cleft epiglottis). The spleen may be missing (asplenia), or be present as multiple small spleens, rather than a single (polyspenia).Heart abnormalities may include atrial and ventricular septal defects (ASDs and VSDs) and patent ductus arteriosus or other more complex malformations. ASDs are characterized by an abnormal opening in the fibrous partition (septum) that separates the two upper chambers (atria) of the heart. VSDs are characterized by an abnormal opening in the septum that divides the heart’s two lower chambers (ventricles). The size, location, and nature of a septal defect and any associated abnormalities determine the severity of symptoms. Patent ductus arteriosus is a condition in which the passage (ductus) between the blood vessel that leads to the lungs (pulmonary artery) and the major artery of the body (aorta) fails to close after birth.Genital abnormalities include external or internal genitalia in both male or female.
| 772 |
Meckel Syndrome
|
nord_772_2
|
Causes of Meckel Syndrome
|
Meckel syndrome can be caused by changes (mutations) in thirteen genes: B9D1, B9D2, CC2D2A, CEP290, MKS1, RPGRIP1L, TCTN2, TCTN3, TMEM67, TMEM107, TMEM216, TMEM231 and TMEM237. Mutations in these 13 genes account for 75 percent of all cases; the remaining 25 percent have unknown genetic causes. Most of these genes are also responsible for a neurological disorder called Joubert syndrome, leading to the concept that Meckel syndrome is the extreme lethal form of Joubert syndrome. The proteins produced by these genes are known to influence cell structures or function called primary cilia. Cilia are microscopic projections that stick out on the surface of the cell and help transmit information in signaling pathways. Cilia are important for many cell functions, in many cell types especially in the kidney, liver, eye and brain. Mutations in these gene cause problems in the function of the primary cilia, resulting in various defects dependent of the cell type. Early defective ciliary function can be responsible for developmental abnormalities, specifically in the kidneys, brain, limbs, heart.Meckel syndrome is inherited as an autosomal recessive genetic condition. 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 altered gene for the disease, the person will be a carrier for the disease, but will not show symptoms. The risk for two carrier parents to both pass the altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is 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 Meckel Syndrome. Meckel syndrome can be caused by changes (mutations) in thirteen genes: B9D1, B9D2, CC2D2A, CEP290, MKS1, RPGRIP1L, TCTN2, TCTN3, TMEM67, TMEM107, TMEM216, TMEM231 and TMEM237. Mutations in these 13 genes account for 75 percent of all cases; the remaining 25 percent have unknown genetic causes. Most of these genes are also responsible for a neurological disorder called Joubert syndrome, leading to the concept that Meckel syndrome is the extreme lethal form of Joubert syndrome. The proteins produced by these genes are known to influence cell structures or function called primary cilia. Cilia are microscopic projections that stick out on the surface of the cell and help transmit information in signaling pathways. Cilia are important for many cell functions, in many cell types especially in the kidney, liver, eye and brain. Mutations in these gene cause problems in the function of the primary cilia, resulting in various defects dependent of the cell type. Early defective ciliary function can be responsible for developmental abnormalities, specifically in the kidneys, brain, limbs, heart.Meckel syndrome is inherited as an autosomal recessive genetic condition. 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 altered gene for the disease, the person will be a carrier for the disease, but will not show symptoms. The risk for two carrier parents to both pass the altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is 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.
| 772 |
Meckel Syndrome
|
nord_772_3
|
Affects of Meckel Syndrome
|
Meckel syndrome affects males and females in equal numbers. More than 200 cases have been reported in the medical literature. The incidence of Meckel syndrome is estimated in various areas around the world to be 1 in 13,250 to 1 in 140,000 live births. The disorder is more common in the Finnish population due to a founder effect, with an incidence of 1 in 9000 and 1 in 3,000 people of Belgian ancestry. However, Gujarati Indians have a prevalence of 1 in 1,300. It occurs more frequently in the context of consanguineous unions.
|
Affects of Meckel Syndrome. Meckel syndrome affects males and females in equal numbers. More than 200 cases have been reported in the medical literature. The incidence of Meckel syndrome is estimated in various areas around the world to be 1 in 13,250 to 1 in 140,000 live births. The disorder is more common in the Finnish population due to a founder effect, with an incidence of 1 in 9000 and 1 in 3,000 people of Belgian ancestry. However, Gujarati Indians have a prevalence of 1 in 1,300. It occurs more frequently in the context of consanguineous unions.
| 772 |
Meckel Syndrome
|
nord_772_4
|
Related disorders of Meckel Syndrome
|
Symptoms of the following disorders can be similar to those of Meckel syndrome. Comparisons may be useful for a differential diagnosis:Smith-Lemli-Opitz (SLO) syndrome is a rare hereditary developmental disorder characterized multiple abnormalities that are present at birth (congenital). Symptoms may include characteristic facial features, microcephaly, growth restriction, intellectual disability, extra fingers or toes (polydactyly), loss of vision, incomplete development of the male genitalia, short nose with displaced nostrils and a smaller than normal size opening of the stomach (pyloric stenosis). In some patients, brain or heart abnormalities may be present. The specific symptoms associated with each person vary greatly. Smith-Lemli-Optiz syndrome is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Smith-Lemli-Opitz” as your search term in the Rare Disease Database.)Trisomy 13 is a chromosomal disorder in which all or a portion of chromosome 13 appears three times (trisomy) rather than twice in cells of the body. In some affected individuals, only a percentage of cells may contain the extra 13th chromosome (mosaicism), whereas other cells contain the normal chromosomal pair. In individuals with Trisomy 13, the range and severity of associated symptoms and findings may depend on the specific location of the duplicated (trisomic) portion of chromosome 13, as well as the percentage of cells containing the abnormality. However, in many affected infants and children, such abnormalities may include developmental delays, profound intellectual disability, unusually small eyes (microphthalmia), an abnormal groove in the upper lip (cleft lip), incomplete closure of the roof of the mouth (cleft palate), undescended testes (cryptorchidism) in affected males, and extra (supernumerary) fingers and toes (polydactyly). Additional malformations of the head and facial (craniofacial) area may also be present, such as a relatively small head (microcephaly) with a sloping forehead; a broad, flat nose; widely set eyes (ocular hypertelorism); vertical skin folds covering the eyes; inner corners (epicanthal folds); scalp defects; and malformed, low-set ears. Affected infants may also have incomplete development of certain regions of the brain (e.g., the forebrain); kidney (renal) malformations; and structural heart (cardiac) defects at birth (congenital). Life-threatening complications may develop during infancy or early childhood. (For more information on this disorder, choose “Trisomy 13” as your search term in the Rare Disease Database.)Short rib-polydactyly syndromes are a group of rare skeletal disorders characterized by growth deficiency resulting in short stature, narrow thorax and abnormally short ribs, and extra fingers and toes (polydactyly). There is significant overlap in the symptoms associated with the various short rib-polydactyly syndromes. Additional findings may include polycystic kidneys, underdevelopment (hypoplasia) of the lungs, genitourinary abnormalities, central nervous system abnormalities, developmental delays, and cleft lip and cleft palate. The severe forms of short rib-polydactyly syndromes include Saldino-Noonan, Majewski, Verma-Naumoff and Beemer-Langer syndromes. These disorders are inherited in an autosomal recessive pattern.
|
Related disorders of Meckel Syndrome. Symptoms of the following disorders can be similar to those of Meckel syndrome. Comparisons may be useful for a differential diagnosis:Smith-Lemli-Opitz (SLO) syndrome is a rare hereditary developmental disorder characterized multiple abnormalities that are present at birth (congenital). Symptoms may include characteristic facial features, microcephaly, growth restriction, intellectual disability, extra fingers or toes (polydactyly), loss of vision, incomplete development of the male genitalia, short nose with displaced nostrils and a smaller than normal size opening of the stomach (pyloric stenosis). In some patients, brain or heart abnormalities may be present. The specific symptoms associated with each person vary greatly. Smith-Lemli-Optiz syndrome is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “Smith-Lemli-Opitz” as your search term in the Rare Disease Database.)Trisomy 13 is a chromosomal disorder in which all or a portion of chromosome 13 appears three times (trisomy) rather than twice in cells of the body. In some affected individuals, only a percentage of cells may contain the extra 13th chromosome (mosaicism), whereas other cells contain the normal chromosomal pair. In individuals with Trisomy 13, the range and severity of associated symptoms and findings may depend on the specific location of the duplicated (trisomic) portion of chromosome 13, as well as the percentage of cells containing the abnormality. However, in many affected infants and children, such abnormalities may include developmental delays, profound intellectual disability, unusually small eyes (microphthalmia), an abnormal groove in the upper lip (cleft lip), incomplete closure of the roof of the mouth (cleft palate), undescended testes (cryptorchidism) in affected males, and extra (supernumerary) fingers and toes (polydactyly). Additional malformations of the head and facial (craniofacial) area may also be present, such as a relatively small head (microcephaly) with a sloping forehead; a broad, flat nose; widely set eyes (ocular hypertelorism); vertical skin folds covering the eyes; inner corners (epicanthal folds); scalp defects; and malformed, low-set ears. Affected infants may also have incomplete development of certain regions of the brain (e.g., the forebrain); kidney (renal) malformations; and structural heart (cardiac) defects at birth (congenital). Life-threatening complications may develop during infancy or early childhood. (For more information on this disorder, choose “Trisomy 13” as your search term in the Rare Disease Database.)Short rib-polydactyly syndromes are a group of rare skeletal disorders characterized by growth deficiency resulting in short stature, narrow thorax and abnormally short ribs, and extra fingers and toes (polydactyly). There is significant overlap in the symptoms associated with the various short rib-polydactyly syndromes. Additional findings may include polycystic kidneys, underdevelopment (hypoplasia) of the lungs, genitourinary abnormalities, central nervous system abnormalities, developmental delays, and cleft lip and cleft palate. The severe forms of short rib-polydactyly syndromes include Saldino-Noonan, Majewski, Verma-Naumoff and Beemer-Langer syndromes. These disorders are inherited in an autosomal recessive pattern.
| 772 |
Meckel Syndrome
|
nord_772_5
|
Diagnosis of Meckel Syndrome
|
A diagnosis of Meckel syndrome is often made on ultrasound during pregnancy or at birth thorough clinical evaluation. Molecular genetic testing can be used to confirm the diagnosis and guide genetic counseling. Prenatal diagnosis is available through ultrasonography as early as 14 weeks, which can detect certain abnormalities (e.g., encephalocele, polydactyly, cystic kidneys and oligohydramnios). Chromosomal analysis may be performed to rule out trisomy 13. Smith Lemli- Opitz syndrome may be excluded by biochemical testing.
|
Diagnosis of Meckel Syndrome. A diagnosis of Meckel syndrome is often made on ultrasound during pregnancy or at birth thorough clinical evaluation. Molecular genetic testing can be used to confirm the diagnosis and guide genetic counseling. Prenatal diagnosis is available through ultrasonography as early as 14 weeks, which can detect certain abnormalities (e.g., encephalocele, polydactyly, cystic kidneys and oligohydramnios). Chromosomal analysis may be performed to rule out trisomy 13. Smith Lemli- Opitz syndrome may be excluded by biochemical testing.
| 772 |
Meckel Syndrome
|
nord_772_6
|
Therapies of Meckel Syndrome
|
Treatment
No curative treatment is currently available for Meckel syndrome which has a constantly fatal outcome due to renal failure and lung hypoplasia. Treatment is symptomatic and supportive.Genetic counseling is recommended for the families.
|
Therapies of Meckel Syndrome. Treatment
No curative treatment is currently available for Meckel syndrome which has a constantly fatal outcome due to renal failure and lung hypoplasia. Treatment is symptomatic and supportive.Genetic counseling is recommended for the families.
| 772 |
Meckel Syndrome
|
nord_773_0
|
Overview of MECP2 Duplication Syndrome
|
MECP2 duplication syndrome is a rare genetic neurodevelopmental disorder characterized by a wide variety of symptoms including low muscle tone (hypotonia), potentially severe intellectual disability, developmental delays, recurrent respiratory infections, speech abnormalities, seizures, and progressive spasticity, a condition characterized by muscle stiffness that is worsened with movement and can be associated with involuntary muscle spasms. Additional symptoms can occur. MECP2 duplication syndrome is caused by the duplication of genetic material on a specific region on the X chromosome (Xq28). This region includes the MECP2 gene and typically several adjacent genes. In most affected individuals, the MECP2 duplication is inherited in an X-linked manner; in rare cases, the duplication may occur randomly for no apparent reason (de novo duplication). The disorder predominantly affects males, but females who carry the duplication on one X chromosome (heterozygotes) may exhibit some signs of the disorder. Rarely, females can develop a severe form of the disorder similar to malesOne of the first descriptions in the medical literature of this disorder as a distinct neurological entity was by Lubs et al. in 1999. The discovery that microduplications involving the MECP2 gene on the X chromosome cause a distinct neurological disorder (now known as MECP2 duplication syndrome) was first reported in the medical literature in 2005. Mutations of the MECP2 gene are known to cause Rett syndrome, a neurological disorder that primarily affects females. These disorders are sometimes grouped together as MECP2-related disorders.
|
Overview of MECP2 Duplication Syndrome. MECP2 duplication syndrome is a rare genetic neurodevelopmental disorder characterized by a wide variety of symptoms including low muscle tone (hypotonia), potentially severe intellectual disability, developmental delays, recurrent respiratory infections, speech abnormalities, seizures, and progressive spasticity, a condition characterized by muscle stiffness that is worsened with movement and can be associated with involuntary muscle spasms. Additional symptoms can occur. MECP2 duplication syndrome is caused by the duplication of genetic material on a specific region on the X chromosome (Xq28). This region includes the MECP2 gene and typically several adjacent genes. In most affected individuals, the MECP2 duplication is inherited in an X-linked manner; in rare cases, the duplication may occur randomly for no apparent reason (de novo duplication). The disorder predominantly affects males, but females who carry the duplication on one X chromosome (heterozygotes) may exhibit some signs of the disorder. Rarely, females can develop a severe form of the disorder similar to malesOne of the first descriptions in the medical literature of this disorder as a distinct neurological entity was by Lubs et al. in 1999. The discovery that microduplications involving the MECP2 gene on the X chromosome cause a distinct neurological disorder (now known as MECP2 duplication syndrome) was first reported in the medical literature in 2005. Mutations of the MECP2 gene are known to cause Rett syndrome, a neurological disorder that primarily affects females. These disorders are sometimes grouped together as MECP2-related disorders.
| 773 |
MECP2 Duplication Syndrome
|
nord_773_1
|
Symptoms of MECP2 Duplication Syndrome
|
MECP2 duplication syndrome is characterized by a wide variety of symptoms. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes influencing the disorder hamper physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.One of the initial signs of MECP2 duplication syndrome may be feeding difficulties during the first few weeks of life likely resulting from diminished muscle tone (hypotonia). Affected children may also experience difficulty swallowing, gastroesophageal reflux and excessive drooling. Affected children will often fail to gain weight or grow at the expected rate for age and gender (failure to thrive) and may be at risk of aspiration, however, some infants experience no recognized problems in the newborn (neonatal) period and concern is not raised until other developmental milestones are missed.Children with MECP2 duplication have moderate to severe intellectual disability and experience delays in attaining developmental milestones including sitting and crawling. Consequently, walking is also delayed and, in some cases, individuals develop an unsteady, uncoordinated gait. This abnormal gait can result in the development of exaggerated inward curvature of the lower spine (lumbar hyperlordosis). As affected individuals grow older, about half may experience neurological regression that ultimately results in the loss of previously acquired skills such as the ability to walk. In many cases the onset of regression is linked to onset of epilepsy.The majority of affected individuals do not develop the ability to talk. Some individuals may be able to speak a few words during early childhood or have a limited use of speech, but frequently this ability is progressively lost during adolescence. Most affected individuals have better receptive language skills (i.e. understanding what is said to them). Rarely, some boys do retain the use of speech into adulthood.In many affected children, hypotonia may progress to spasticity, a condition that is generally defined in the medical literature as an abnormal increase in muscle tone or stiffness of affected muscles. Spasticity can be associated with muscle spasms, increased deep tendon reflexes, and fixed joints (contractures). Spasticity affects the legs more severely and, over time, mild to severe contractures of the hips, knees and ankles may develop. A contracture is a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint.Up to half of individuals develop recurrent seizures (epilepsy) in childhood or adolescence. However, the true prevalence of seizures by adulthood may be higher. In some individuals, seizures may not respond to treatment (refractory) and the onset and severity of seizures may correlate with neurological deterioration (e.g. loss of speech, hand use, and ambulation). Seizure types that have been reported in individuals with MECP2 duplication syndrome include head/neck and trunk drop attacks, absence seizures, myoclonic seizures, and generalized or secondarily generalized tonic-clonic or simply tonic seizures (once known as grand mal seizures).Some individuals with MECP2 duplication syndrome experience dysfunction of the immune system, which causes them to be prone to recurrent infections such as respiratory tract infections. Affected individuals may develop recurrent pneumonia that is sometimes severe requiring mechanical ventilation. Middle ear infections (otitis media) and sinusitis are also common. Additional infections have been reported including meningitis or urinary tract infections. Recurrent infections can cause life-threatening complications, and are a major contributing factor for reduced life-expectancy.Many individuals with MECP2 duplication syndrome meet formal criteria for diagnosis with an autism spectrum disorder due to poor expressive language skills, abnormal social affect, and restricted/repetitive behaviors. Mood disorders such as anxiety sometimes occur.Affected individuals often have clinically significant constipation. Bladder dysfunction has also been seen. According to some reports, affected individuals may have chronic intestinal pseudo-obstruction (CIP), a condition characterized by abnormalities affecting the involuntary, coordinated muscular contractions (peristalsis) that propels food and other material through the digestive system. Symptoms may develop due to obstruction of the small bowel and can include nausea, vomiting, abdominal pain, abdominal swelling and constipation. Ultimately, normal nutritional requirements cannot be met leading to unintended weight loss and malnourishment. The acute onset of GI symptoms such as abdominal pain, unusual distension, or vomiting warrants urgent medical evaluation as it can precede life-threatening complications.Individuals with MECP2 duplication may have distinctive facial features including an abnormally flat back of the head (brachycephaly), underdevelopment of the middle of the face (midface hypoplasia), ear anomalies, large ears, deep-set eyes, prominent chin, pointed nose, and an abnormally flat bridge of the nose.Additional findings have been reported in some children with MECP2 duplication syndrome including some degree of growth retardation. Early in life, head size appears to be normal, but as the boys get older, some might develop abnormally small head circumference (microcephaly). However, large head circumference (macrocephaly) has also been observed, and overall these are not consistent features of the syndrome.Some boys have underdeveloped (hypoplastic) genitalia. Affected males may experience failure of the testes to descend (cryptorchidism) and have the urinary opening located on the underside of the penis (hypospadias) rather than at the end.AFFECTED FEMALES
Although MECP2 duplication syndrome is primarily associated with males, females can develop mild symptoms of the disorder or, rarely, a severe form of the disorder. Some researchers have noted that women who have a MECP2 duplication on one of their X chromosomes (heterozygote or carrier females) may be prone to developing neuropsychiatric features including depression, anxiety, and specific personality traits. In addition, recent reports have identified women (i.e., women with unfavorable X-linked inactivation) who developed some symptoms of the disorder including recurrent infections, poor speech development, or seizures.Rarely, females may have a genetic abnormality, known as a translocation, which involves the X chromosome and a non-sex chromosome (autosome). Females with this specific underlying genetic abnormality may develop a severe form of the disorder similar to that seen in males. For more information, on X-linked inactivation and translocations, see the Causes section below.
|
Symptoms of MECP2 Duplication Syndrome. MECP2 duplication syndrome is characterized by a wide variety of symptoms. Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes influencing the disorder hamper physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.One of the initial signs of MECP2 duplication syndrome may be feeding difficulties during the first few weeks of life likely resulting from diminished muscle tone (hypotonia). Affected children may also experience difficulty swallowing, gastroesophageal reflux and excessive drooling. Affected children will often fail to gain weight or grow at the expected rate for age and gender (failure to thrive) and may be at risk of aspiration, however, some infants experience no recognized problems in the newborn (neonatal) period and concern is not raised until other developmental milestones are missed.Children with MECP2 duplication have moderate to severe intellectual disability and experience delays in attaining developmental milestones including sitting and crawling. Consequently, walking is also delayed and, in some cases, individuals develop an unsteady, uncoordinated gait. This abnormal gait can result in the development of exaggerated inward curvature of the lower spine (lumbar hyperlordosis). As affected individuals grow older, about half may experience neurological regression that ultimately results in the loss of previously acquired skills such as the ability to walk. In many cases the onset of regression is linked to onset of epilepsy.The majority of affected individuals do not develop the ability to talk. Some individuals may be able to speak a few words during early childhood or have a limited use of speech, but frequently this ability is progressively lost during adolescence. Most affected individuals have better receptive language skills (i.e. understanding what is said to them). Rarely, some boys do retain the use of speech into adulthood.In many affected children, hypotonia may progress to spasticity, a condition that is generally defined in the medical literature as an abnormal increase in muscle tone or stiffness of affected muscles. Spasticity can be associated with muscle spasms, increased deep tendon reflexes, and fixed joints (contractures). Spasticity affects the legs more severely and, over time, mild to severe contractures of the hips, knees and ankles may develop. A contracture is a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint.Up to half of individuals develop recurrent seizures (epilepsy) in childhood or adolescence. However, the true prevalence of seizures by adulthood may be higher. In some individuals, seizures may not respond to treatment (refractory) and the onset and severity of seizures may correlate with neurological deterioration (e.g. loss of speech, hand use, and ambulation). Seizure types that have been reported in individuals with MECP2 duplication syndrome include head/neck and trunk drop attacks, absence seizures, myoclonic seizures, and generalized or secondarily generalized tonic-clonic or simply tonic seizures (once known as grand mal seizures).Some individuals with MECP2 duplication syndrome experience dysfunction of the immune system, which causes them to be prone to recurrent infections such as respiratory tract infections. Affected individuals may develop recurrent pneumonia that is sometimes severe requiring mechanical ventilation. Middle ear infections (otitis media) and sinusitis are also common. Additional infections have been reported including meningitis or urinary tract infections. Recurrent infections can cause life-threatening complications, and are a major contributing factor for reduced life-expectancy.Many individuals with MECP2 duplication syndrome meet formal criteria for diagnosis with an autism spectrum disorder due to poor expressive language skills, abnormal social affect, and restricted/repetitive behaviors. Mood disorders such as anxiety sometimes occur.Affected individuals often have clinically significant constipation. Bladder dysfunction has also been seen. According to some reports, affected individuals may have chronic intestinal pseudo-obstruction (CIP), a condition characterized by abnormalities affecting the involuntary, coordinated muscular contractions (peristalsis) that propels food and other material through the digestive system. Symptoms may develop due to obstruction of the small bowel and can include nausea, vomiting, abdominal pain, abdominal swelling and constipation. Ultimately, normal nutritional requirements cannot be met leading to unintended weight loss and malnourishment. The acute onset of GI symptoms such as abdominal pain, unusual distension, or vomiting warrants urgent medical evaluation as it can precede life-threatening complications.Individuals with MECP2 duplication may have distinctive facial features including an abnormally flat back of the head (brachycephaly), underdevelopment of the middle of the face (midface hypoplasia), ear anomalies, large ears, deep-set eyes, prominent chin, pointed nose, and an abnormally flat bridge of the nose.Additional findings have been reported in some children with MECP2 duplication syndrome including some degree of growth retardation. Early in life, head size appears to be normal, but as the boys get older, some might develop abnormally small head circumference (microcephaly). However, large head circumference (macrocephaly) has also been observed, and overall these are not consistent features of the syndrome.Some boys have underdeveloped (hypoplastic) genitalia. Affected males may experience failure of the testes to descend (cryptorchidism) and have the urinary opening located on the underside of the penis (hypospadias) rather than at the end.AFFECTED FEMALES
Although MECP2 duplication syndrome is primarily associated with males, females can develop mild symptoms of the disorder or, rarely, a severe form of the disorder. Some researchers have noted that women who have a MECP2 duplication on one of their X chromosomes (heterozygote or carrier females) may be prone to developing neuropsychiatric features including depression, anxiety, and specific personality traits. In addition, recent reports have identified women (i.e., women with unfavorable X-linked inactivation) who developed some symptoms of the disorder including recurrent infections, poor speech development, or seizures.Rarely, females may have a genetic abnormality, known as a translocation, which involves the X chromosome and a non-sex chromosome (autosome). Females with this specific underlying genetic abnormality may develop a severe form of the disorder similar to that seen in males. For more information, on X-linked inactivation and translocations, see the Causes section below.
| 773 |
MECP2 Duplication Syndrome
|
nord_773_2
|
Causes of MECP2 Duplication Syndrome
|
MECP2 duplication syndrome is caused by a genetic abnormality in which a portion of the X chromosome appears two times on one of the X chromosomes (duplication) instead of once. By definition, the affected region always contains the methyl-CpG-binding protein 2 (MECP2) gene. Most affected children have very small duplications called microduplications, but larger, more complex rearrangements (e.g. translocations) can also cause the disorder. Depending upon the exact size and location of the duplicated area, additional genes are also duplicated. The duplication size is unique to each affected family or individual.The MECP2 gene contains instructions for producing (encoding) a protein called MeCP2. This protein is essential for normal brain function and most likely has several different functions in the body. Researchers believe that the protein may regulate other genes in the brain by fine tuning the levels of those genes. The presence of an extra copy of the MECP2 gene leads to overproduction (overexpression) of the MeCP2 protein. This overexpression is believed to increase the activity of the protein. Researchers believe that the more excess protein produced, the worse the associated symptoms. Rarely, affected males have MECP2 triplication, in which there are two extra copies of the MECP2 gene for a total of three. In these cases, MeCP2 overexpression is greater and the associated symptoms have been more severe.Researchers have recently discovered that MeCP2 overexpression can impair the function of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending against different infectious agents (i.e. invading microscopic life-forms [microorganisms]). One specific part of the immune system affected in this disorder is the T cell system, which helps to fight several viruses, some bacteria and yeast and fungi. Researchers believe that MeCP2 overexpression suppresses the secretion of a protein known as interferon-gamma from certain T cells, as well as lower levels of immunoglobulins IgA, IgG and IgM, leading to a partially immunodeficient state. Low tone, gastrointestinal reflux and swallowing dysfunction may additionally predispose to recurrent respiratory tract infections and pneumonias. More research is necessary to determine the specific pathogens that affect individuals with MECP2 duplication syndrome and how to best treat the abnormal immune system.Most affected males inherit the disorder from a carrier mother who has favorable survival of the X-chromosome carrying the one normal copy of MECP2 as the active X chromosome. Such carrier females either have no symptoms or extremely mild symptoms such as anxiety or mild symptoms of the disorder. When a mother is a known carrier of the MECP2 mutation, there is a 50% chance of passing that mutation on to her children. In extremely rare cases, the duplication that causes the disorder occurs randomly for no apparent reason (de novo duplication). Affected males can also develop the disorder due to a translocation involving the X chromosome and a non-sex chromosome (autosome). In such cases, the parent’s chromosomes are unaffected and the disorder is not inherited.Random X-chromosome inactivation is a normal process in females. Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. In females, certain disease traits on the X chromosome such as a mutated gene may be “masked” by the normal gene on the other X chromosome (random X-chromosome inactivation). Basically, in each cell of the body one X chromosome is active and one is turned off or “silenced”. This occurs randomly and generally happens as a 50-50 split. However, some females may have favorable X-inactivation, in which the affected X chromosome is silenced in most of the cells and these females may only have mild symptoms of the disorder. Other females may have unfavorable X-inactivation, in which the unaffected X chromosome is silenced in most of the cells and these females usually have a severe expression of the disorder.In the initial reports, most women with a MECP2 duplication have had preferentially favorable X-inactivation (near 100% inactivation of the duplication-bearing X chromosome). As previously discussed, these women generally have no symptoms or only mild symptoms of the disorder. However, recent reports have identified women in whom the percentage of cells with the duplication-bearing X chromosome is more numerous. Consequently, these women have developed symptoms of the disorder.Rarely, females with a MECP2 duplication have developed a severe form of the disorder similar to that seen in affected males. This occurs when an additional (concomitant) abnormality involving the X chromosome occurs, such as an unbalanced translocation. An unbalanced translocation occurs when a region of one chromosome breaks off and is attached to another chromosome, causing a shifting of genetic material. In these specific cases, the Xq28 region breaks off and attaches to an autosome (non-sex chromosome). Because the duplicated material on the X chromosome has been translocated to an autosome, this prevents the normal X-inactivation of the duplicated segment. An unbalanced translocation occurs randomly (de novo).Unbalanced translocation involving the Xq segment can also cause MECP2 duplication syndrome in males. Translocation between the Xq segment and short arm (p) of the X chromosome, the Y chromosome, or an autosome has been reported.As mentioned above, additional genes can be involved in the duplicated area on the X chromosome. These genes include IRAK1, L1CAM, FLNA and many others. It is possible that these genes contribute to the overall spectrum of disease associated with MECP2 duplication syndrome. The IRAK1 gene, which is involved in the immune system, is typically duplicated as well, even in individuals with very small duplications. Many individuals with very small duplications, involving only the MECP2 and IRAK1 genes, have developed the core symptoms associated with the disorder. However, larger duplications that contain additional genes may be associated with other symptoms. For example, the FLNA gene is associated with gastrointestinal problems such as pseudo-obstruction and may be associated with a distinct clinical phenotype involving this condition. The exact role that these adjacent genes play in the development of MECP2 duplication syndrome is not fully understood.Though plausible, no clear indication has so far been found that involvement of additional genes modifies the expression of MECP2 duplication syndrome, despite several studies having looked at a potential association.More research is necessary to determine to what extent additional genes influence the development of MECP2 duplication syndrome.
|
Causes of MECP2 Duplication Syndrome. MECP2 duplication syndrome is caused by a genetic abnormality in which a portion of the X chromosome appears two times on one of the X chromosomes (duplication) instead of once. By definition, the affected region always contains the methyl-CpG-binding protein 2 (MECP2) gene. Most affected children have very small duplications called microduplications, but larger, more complex rearrangements (e.g. translocations) can also cause the disorder. Depending upon the exact size and location of the duplicated area, additional genes are also duplicated. The duplication size is unique to each affected family or individual.The MECP2 gene contains instructions for producing (encoding) a protein called MeCP2. This protein is essential for normal brain function and most likely has several different functions in the body. Researchers believe that the protein may regulate other genes in the brain by fine tuning the levels of those genes. The presence of an extra copy of the MECP2 gene leads to overproduction (overexpression) of the MeCP2 protein. This overexpression is believed to increase the activity of the protein. Researchers believe that the more excess protein produced, the worse the associated symptoms. Rarely, affected males have MECP2 triplication, in which there are two extra copies of the MECP2 gene for a total of three. In these cases, MeCP2 overexpression is greater and the associated symptoms have been more severe.Researchers have recently discovered that MeCP2 overexpression can impair the function of the immune system. The immune system is divided into several components, the combined actions of which are responsible for defending against different infectious agents (i.e. invading microscopic life-forms [microorganisms]). One specific part of the immune system affected in this disorder is the T cell system, which helps to fight several viruses, some bacteria and yeast and fungi. Researchers believe that MeCP2 overexpression suppresses the secretion of a protein known as interferon-gamma from certain T cells, as well as lower levels of immunoglobulins IgA, IgG and IgM, leading to a partially immunodeficient state. Low tone, gastrointestinal reflux and swallowing dysfunction may additionally predispose to recurrent respiratory tract infections and pneumonias. More research is necessary to determine the specific pathogens that affect individuals with MECP2 duplication syndrome and how to best treat the abnormal immune system.Most affected males inherit the disorder from a carrier mother who has favorable survival of the X-chromosome carrying the one normal copy of MECP2 as the active X chromosome. Such carrier females either have no symptoms or extremely mild symptoms such as anxiety or mild symptoms of the disorder. When a mother is a known carrier of the MECP2 mutation, there is a 50% chance of passing that mutation on to her children. In extremely rare cases, the duplication that causes the disorder occurs randomly for no apparent reason (de novo duplication). Affected males can also develop the disorder due to a translocation involving the X chromosome and a non-sex chromosome (autosome). In such cases, the parent’s chromosomes are unaffected and the disorder is not inherited.Random X-chromosome inactivation is a normal process in females. Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. In females, certain disease traits on the X chromosome such as a mutated gene may be “masked” by the normal gene on the other X chromosome (random X-chromosome inactivation). Basically, in each cell of the body one X chromosome is active and one is turned off or “silenced”. This occurs randomly and generally happens as a 50-50 split. However, some females may have favorable X-inactivation, in which the affected X chromosome is silenced in most of the cells and these females may only have mild symptoms of the disorder. Other females may have unfavorable X-inactivation, in which the unaffected X chromosome is silenced in most of the cells and these females usually have a severe expression of the disorder.In the initial reports, most women with a MECP2 duplication have had preferentially favorable X-inactivation (near 100% inactivation of the duplication-bearing X chromosome). As previously discussed, these women generally have no symptoms or only mild symptoms of the disorder. However, recent reports have identified women in whom the percentage of cells with the duplication-bearing X chromosome is more numerous. Consequently, these women have developed symptoms of the disorder.Rarely, females with a MECP2 duplication have developed a severe form of the disorder similar to that seen in affected males. This occurs when an additional (concomitant) abnormality involving the X chromosome occurs, such as an unbalanced translocation. An unbalanced translocation occurs when a region of one chromosome breaks off and is attached to another chromosome, causing a shifting of genetic material. In these specific cases, the Xq28 region breaks off and attaches to an autosome (non-sex chromosome). Because the duplicated material on the X chromosome has been translocated to an autosome, this prevents the normal X-inactivation of the duplicated segment. An unbalanced translocation occurs randomly (de novo).Unbalanced translocation involving the Xq segment can also cause MECP2 duplication syndrome in males. Translocation between the Xq segment and short arm (p) of the X chromosome, the Y chromosome, or an autosome has been reported.As mentioned above, additional genes can be involved in the duplicated area on the X chromosome. These genes include IRAK1, L1CAM, FLNA and many others. It is possible that these genes contribute to the overall spectrum of disease associated with MECP2 duplication syndrome. The IRAK1 gene, which is involved in the immune system, is typically duplicated as well, even in individuals with very small duplications. Many individuals with very small duplications, involving only the MECP2 and IRAK1 genes, have developed the core symptoms associated with the disorder. However, larger duplications that contain additional genes may be associated with other symptoms. For example, the FLNA gene is associated with gastrointestinal problems such as pseudo-obstruction and may be associated with a distinct clinical phenotype involving this condition. The exact role that these adjacent genes play in the development of MECP2 duplication syndrome is not fully understood.Though plausible, no clear indication has so far been found that involvement of additional genes modifies the expression of MECP2 duplication syndrome, despite several studies having looked at a potential association.More research is necessary to determine to what extent additional genes influence the development of MECP2 duplication syndrome.
| 773 |
MECP2 Duplication Syndrome
|
nord_773_3
|
Affects of MECP2 Duplication Syndrome
|
The exact incidence and prevalence of MECP2 duplication syndrome in the general population is unknown. Because affected individuals may go undiagnosed or misdiagnosed, determining the disorder’s true frequency in the general population is difficult. Well over 200 individuals have been reported in the medical literature. It has been estimated that approximately 1-2% of unexplained cases of X-linked intellectual disability may be due to MECP2 duplication syndrome.
|
Affects of MECP2 Duplication Syndrome. The exact incidence and prevalence of MECP2 duplication syndrome in the general population is unknown. Because affected individuals may go undiagnosed or misdiagnosed, determining the disorder’s true frequency in the general population is difficult. Well over 200 individuals have been reported in the medical literature. It has been estimated that approximately 1-2% of unexplained cases of X-linked intellectual disability may be due to MECP2 duplication syndrome.
| 773 |
MECP2 Duplication Syndrome
|
nord_773_4
|
Related disorders of MECP2 Duplication Syndrome
|
Symptoms of the following disorders can be similar to those of MECP2 duplication syndrome. Comparisons may be useful for a differential diagnosis.Alpha thalassemia X-linked intellectual disability (ATR-X) syndrome is a rare genetic disorder affecting multiple organ systems of the body. ATR-X syndrome is characterized by intellectual disability, characteristic facial features, abnormalities of the genitourinary tract, and alpha thalassemia. Alpha thalassemia, which is a condition where there is a defect in the production of the oxygen-carrying pigments of red blood cells (hemoglobin), is not seen in every case. Additional abnormalities are usually present in most cases. ATR-X syndrome is inherited as an X-linked recessive genetic condition. (For more information on this disorder, choose “ATR-X” as your search term in the Rare Disease Database.)L1 syndrome is an inherited, X-linked disorder occurring in males that primarily affects the nervous system. The disease is mainly characterized by hydrocephalus (increased cerebrospinal fluid in the center of the brain), spasticity of the lower limbs (muscle stiffness), adducted thumbs (clasped towards the palm), aphasia (difficulty with speaking), seizures, and agenesis of the corpus callosum (underdeveloped or absent connecting tissue between the left and right hemispheres of the brain). Affected individuals have intellectual disability in the mild to moderate range. L1 syndrome is caused by abnormalities (mutations) in the L1CAM gene, which affects about 1 in 30,000 males. (For more information on this disorder, choose “L1 syndrome” as your search term in the Rare Disease Database.)There are additional X-linked disorders that cause intellectual disability and other symptoms that may be similar to those seen in MECP2 duplication syndrome. These disorders usually have other, distinguishing features. Such disorders include Lowe syndrome, Coffin-Lowry syndrome, MCT8-specific thyroid hormone cell transporter deficiency (Allan-Dudley-Herndon syndrome), Renpenning syndrome, and Juberg-Marsidi syndrome. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)
|
Related disorders of MECP2 Duplication Syndrome. Symptoms of the following disorders can be similar to those of MECP2 duplication syndrome. Comparisons may be useful for a differential diagnosis.Alpha thalassemia X-linked intellectual disability (ATR-X) syndrome is a rare genetic disorder affecting multiple organ systems of the body. ATR-X syndrome is characterized by intellectual disability, characteristic facial features, abnormalities of the genitourinary tract, and alpha thalassemia. Alpha thalassemia, which is a condition where there is a defect in the production of the oxygen-carrying pigments of red blood cells (hemoglobin), is not seen in every case. Additional abnormalities are usually present in most cases. ATR-X syndrome is inherited as an X-linked recessive genetic condition. (For more information on this disorder, choose “ATR-X” as your search term in the Rare Disease Database.)L1 syndrome is an inherited, X-linked disorder occurring in males that primarily affects the nervous system. The disease is mainly characterized by hydrocephalus (increased cerebrospinal fluid in the center of the brain), spasticity of the lower limbs (muscle stiffness), adducted thumbs (clasped towards the palm), aphasia (difficulty with speaking), seizures, and agenesis of the corpus callosum (underdeveloped or absent connecting tissue between the left and right hemispheres of the brain). Affected individuals have intellectual disability in the mild to moderate range. L1 syndrome is caused by abnormalities (mutations) in the L1CAM gene, which affects about 1 in 30,000 males. (For more information on this disorder, choose “L1 syndrome” as your search term in the Rare Disease Database.)There are additional X-linked disorders that cause intellectual disability and other symptoms that may be similar to those seen in MECP2 duplication syndrome. These disorders usually have other, distinguishing features. Such disorders include Lowe syndrome, Coffin-Lowry syndrome, MCT8-specific thyroid hormone cell transporter deficiency (Allan-Dudley-Herndon syndrome), Renpenning syndrome, and Juberg-Marsidi syndrome. (For more information on this disorder, choose the specific disorder name as your search term in the Rare Disease Database.)
| 773 |
MECP2 Duplication Syndrome
|
nord_773_5
|
Diagnosis of MECP2 Duplication Syndrome
|
A diagnosis of MECP2 duplication syndrome is based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. It should be included in the differential diagnosis of male infants with hypotonia.Clinical Testing and Workup
There are a variety of tests that can be used to diagnose MECP2 duplication syndrome including array comparative genomic hybridization (array-CGH). This test can detect the gain or loss of chromosomal material including microduplications. In rare instances, when a current array-CGH does not detect a change in genetic material, whole exome or even whole genome sequencing can be utilized, a sophisticated technique that determines the complete DNA sequence (or, in the case of whole exome, the sequence of the expressed part of the DNA) of an individual.Additional tests that can confirm CGH results or for direct clinical testing include polymerase chain reaction (PCR), fluorescent is situ hybridization (FISH) analysis, chromosome microarray SNP analysis, and multiplex ligation-dependent probe amplification (MLPA). PCR is a laboratory technique that has been described as “photocopying”. It enables researchers to enlarge and repeatedly copy sequences of DNA. As a result, they are able to closely analyze DNA and more easily identify genes and genetic changes.A FISH test can be used to determine a person’s karyotype. A karyotype is a visual representation of a person’s chromosomal makeup (i.e. the 46 chromosomes in a cell). The FISH test can detect chromosomal abnormalities such as duplications or translocation.Chromosome microarray SNP analysis uses probes that can detect chromosomal abnormalities including microduplications, including those that are the underlying cause of many cases of MECP2 duplication syndrome.The MLPA test is a relatively new method for assessing chromosomes and can detect certain chromosomal abnormalities including those associated with MECP2 duplication syndrome. Pre-implantation genetic diagnosis (PGD) may be an option when a parent has a known genetic abnormality (i.e. carrier mother). PGD can be performed on embryos created through in vitro fertilization. PGD refers to testing an embryo to determine whether it has the same genetic abnormality as the parent. Families interested such an option should seek the counsel of a certified genetics professional.
|
Diagnosis of MECP2 Duplication Syndrome. A diagnosis of MECP2 duplication syndrome is based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. It should be included in the differential diagnosis of male infants with hypotonia.Clinical Testing and Workup
There are a variety of tests that can be used to diagnose MECP2 duplication syndrome including array comparative genomic hybridization (array-CGH). This test can detect the gain or loss of chromosomal material including microduplications. In rare instances, when a current array-CGH does not detect a change in genetic material, whole exome or even whole genome sequencing can be utilized, a sophisticated technique that determines the complete DNA sequence (or, in the case of whole exome, the sequence of the expressed part of the DNA) of an individual.Additional tests that can confirm CGH results or for direct clinical testing include polymerase chain reaction (PCR), fluorescent is situ hybridization (FISH) analysis, chromosome microarray SNP analysis, and multiplex ligation-dependent probe amplification (MLPA). PCR is a laboratory technique that has been described as “photocopying”. It enables researchers to enlarge and repeatedly copy sequences of DNA. As a result, they are able to closely analyze DNA and more easily identify genes and genetic changes.A FISH test can be used to determine a person’s karyotype. A karyotype is a visual representation of a person’s chromosomal makeup (i.e. the 46 chromosomes in a cell). The FISH test can detect chromosomal abnormalities such as duplications or translocation.Chromosome microarray SNP analysis uses probes that can detect chromosomal abnormalities including microduplications, including those that are the underlying cause of many cases of MECP2 duplication syndrome.The MLPA test is a relatively new method for assessing chromosomes and can detect certain chromosomal abnormalities including those associated with MECP2 duplication syndrome. Pre-implantation genetic diagnosis (PGD) may be an option when a parent has a known genetic abnormality (i.e. carrier mother). PGD can be performed on embryos created through in vitro fertilization. PGD refers to testing an embryo to determine whether it has the same genetic abnormality as the parent. Families interested such an option should seek the counsel of a certified genetics professional.
| 773 |
MECP2 Duplication Syndrome
|
nord_773_6
|
Therapies of MECP2 Duplication Syndrome
|
Treatment
The treatment of MECP2 duplication syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, pediatric neurologists, gastroenterologists, psychiatrists, speech pathologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may be of benefit for affected individuals and their families.Treatment options that may be used to treat individuals with MECP2 duplication syndrome are complex and varied. The specific treatment plan will need to be highly individualized. Decisions concerning the use of specific treatments should be made by physicians and other members of the health care team in careful consultation with an affected child’s parents or with an adult patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Inclusion of novel augmentative communication devices, such as eye-tracking technology based communication devices, in the therapy regimen are encouraged. It is essential that therapies are continued on a year-round basis to promote development of new skills and to prevent regression. Some children who lose skills are able to re-learn them with intensive therapy. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.Other treatment is symptomatic and supportive. Additional therapies for MECP2 duplication syndrome depend upon the specific abnormalities present and generally follow standard guidelines.Some general therapies common for infants or children include monitoring feeding and swallowing difficulties. Insertion of a feeding tube through a surgical opening in the stomach (gastrostomy) may be necessary to ensure proper nutritional support and to prevent aspiration.Drugs may be used to treat a variety of symptoms associated with MECP2 duplication syndrome. Anti-seizure medications (anti-convulsants) are usually effective in treating seizures; however, in a significant subset of cases these medications do not completely control seizures (refractory seizures) and complementary approaches such as some implementation of the ketogenic diet, or implantation of a vagus nerve stimulator may be sought. Drugs may be used to improve spasticity and muscle rigidity, but can also be ineffective or even potentially worsen the condition. Working with a physical medicine and rehabilitation specialist to treat spasticity is recommended. Prompt treatment of spasticity may prevent the development of contractures.Because of the susceptibility to infections, when affected individuals develop an infection, they should be treated immediately and aggressively with appropriate antibiotics. Recurrent infections, especially respiratory infections, can be severe enough to necessitate hospitalization and require assisted (mechanical) ventilation. Individuals who develop recurrent pneumonia should be evaluated by an immunology specialist since medical interventions including the use of prophylactic antibiotics and/or immunoglobulin therapy are indicated in some cases.
|
Therapies of MECP2 Duplication Syndrome. Treatment
The treatment of MECP2 duplication syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, pediatric neurologists, gastroenterologists, psychiatrists, speech pathologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may be of benefit for affected individuals and their families.Treatment options that may be used to treat individuals with MECP2 duplication syndrome are complex and varied. The specific treatment plan will need to be highly individualized. Decisions concerning the use of specific treatments should be made by physicians and other members of the health care team in careful consultation with an affected child’s parents or with an adult patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Various methods of rehabilitative and behavioral therapy may be beneficial. Inclusion of novel augmentative communication devices, such as eye-tracking technology based communication devices, in the therapy regimen are encouraged. It is essential that therapies are continued on a year-round basis to promote development of new skills and to prevent regression. Some children who lose skills are able to re-learn them with intensive therapy. Additional medical, social and/or vocational services including special remedial education may be necessary. Psychosocial support for the entire family is essential as well.Other treatment is symptomatic and supportive. Additional therapies for MECP2 duplication syndrome depend upon the specific abnormalities present and generally follow standard guidelines.Some general therapies common for infants or children include monitoring feeding and swallowing difficulties. Insertion of a feeding tube through a surgical opening in the stomach (gastrostomy) may be necessary to ensure proper nutritional support and to prevent aspiration.Drugs may be used to treat a variety of symptoms associated with MECP2 duplication syndrome. Anti-seizure medications (anti-convulsants) are usually effective in treating seizures; however, in a significant subset of cases these medications do not completely control seizures (refractory seizures) and complementary approaches such as some implementation of the ketogenic diet, or implantation of a vagus nerve stimulator may be sought. Drugs may be used to improve spasticity and muscle rigidity, but can also be ineffective or even potentially worsen the condition. Working with a physical medicine and rehabilitation specialist to treat spasticity is recommended. Prompt treatment of spasticity may prevent the development of contractures.Because of the susceptibility to infections, when affected individuals develop an infection, they should be treated immediately and aggressively with appropriate antibiotics. Recurrent infections, especially respiratory infections, can be severe enough to necessitate hospitalization and require assisted (mechanical) ventilation. Individuals who develop recurrent pneumonia should be evaluated by an immunology specialist since medical interventions including the use of prophylactic antibiotics and/or immunoglobulin therapy are indicated in some cases.
| 773 |
MECP2 Duplication Syndrome
|
nord_774_0
|
Overview of Median Arcuate Ligament Syndrome
|
The median arcuate ligament syndrome (MALS) is a cause of chronic abdominal pain affecting both children and adults alike. Chronic abdominal pain is a very common condition that can have significant negative, long-term psychosocial consequences, including increased risk for anxiety, school and work absences, poor functional capacity, and a poor quality of life. While the exact cause of the pain is unknown, compression of the celiac artery and/or the celiac plexus nerves by the diaphragm can result in pain that is worsened with eating or sometimes with exercise. Other symptoms include nausea and weight loss. In some patients the symptoms can be devastating and can lead to erroneous diagnoses of an eating disorder, psychiatric conditions, or functional abdominal pain (e.g. irritable bowel syndrome, abdominal migraine). The diagnosis is made based on a combination of the clinical symptoms and radiology imaging. There is a surgical procedure that can be performed that is effective in approximately 60-80% of patients.
|
Overview of Median Arcuate Ligament Syndrome. The median arcuate ligament syndrome (MALS) is a cause of chronic abdominal pain affecting both children and adults alike. Chronic abdominal pain is a very common condition that can have significant negative, long-term psychosocial consequences, including increased risk for anxiety, school and work absences, poor functional capacity, and a poor quality of life. While the exact cause of the pain is unknown, compression of the celiac artery and/or the celiac plexus nerves by the diaphragm can result in pain that is worsened with eating or sometimes with exercise. Other symptoms include nausea and weight loss. In some patients the symptoms can be devastating and can lead to erroneous diagnoses of an eating disorder, psychiatric conditions, or functional abdominal pain (e.g. irritable bowel syndrome, abdominal migraine). The diagnosis is made based on a combination of the clinical symptoms and radiology imaging. There is a surgical procedure that can be performed that is effective in approximately 60-80% of patients.
| 774 |
Median Arcuate Ligament Syndrome
|
nord_774_1
|
Symptoms of Median Arcuate Ligament Syndrome
|
Compression of the celiac artery by the median arcuate ligament is a poorly understood vascular compression syndrome involving the celiac artery and celiac nerve plexus that results in upper abdominal pain (frequently made worse with eating), weight loss, nausea and vomiting. Sometimes a doctor may hear a soft whooshing sound with a stethoscope (bruit) over the upper abdomen that may mean there is a vascular blockage. Some patients who are athletes may experience recurrent upper abdominal pain that is brought on by moderate to intense cardiovascular work outs. Additional symptoms associated with the diagnosis, but frequently indicative of other medical problems include palpitations (hearing or feeling your own heartbeat), chest pain, diarrhea, constipation, and difficulty sleeping.
|
Symptoms of Median Arcuate Ligament Syndrome. Compression of the celiac artery by the median arcuate ligament is a poorly understood vascular compression syndrome involving the celiac artery and celiac nerve plexus that results in upper abdominal pain (frequently made worse with eating), weight loss, nausea and vomiting. Sometimes a doctor may hear a soft whooshing sound with a stethoscope (bruit) over the upper abdomen that may mean there is a vascular blockage. Some patients who are athletes may experience recurrent upper abdominal pain that is brought on by moderate to intense cardiovascular work outs. Additional symptoms associated with the diagnosis, but frequently indicative of other medical problems include palpitations (hearing or feeling your own heartbeat), chest pain, diarrhea, constipation, and difficulty sleeping.
| 774 |
Median Arcuate Ligament Syndrome
|
nord_774_2
|
Causes of Median Arcuate Ligament Syndrome
|
The median arcuate ligament is formed by the merging of the right and left attachments of the diaphragm as they cross over the aorta as it enters the abdominal cavity from the chest. The relationship of the ligament to the celiac artery origin determines compression: when the celiac artery comes off the aorta above the diaphragm, this can result in compression; when the celiac artery branches off the aorta below the diaphragm, there is no compression. In a study of 75 autopsies, the median arcuate ligament crossed the celiac artery origin entirely (33%) or partially (48%) in a majority of individuals, resulting in significant celiac artery compression.1Since 13-50% of healthy asymptomatic patients have a form of celiac artery compression and a much smaller percentage of these patients actually report symptoms consistent with MALS,2 there is significant debate amongst doctors regarding the existence, the causes, and the management of MALS. The cause of the symptoms is thought to be due to either poor blood flow from celiac artery compression, nerve irritation from compression celiac nerve plexus, or a combination of both. Compression of the celiac artery may result in blood flow coming from another abdominal blood vessel (the superior mesenteric artery) and going to the stomach and liver when a patient eats. This is known as a “steal phenomenon” and a possible cause of abdominal pain.3-5 Another theory is that the nerves in the area of the celiac artery (the peri-aortic ganglia and celiac nerve plexus) are also thought to be overstimulated leading to spasm (vasoconstriction) of the arteries going to the stomach and small bowel and this results in symptoms. Another theory is the compression of the nerves causes interference of the brain/stomach (neuro-enteric) pain pathways resulting in hypersensitivity and pain in the stomach. Common surgical teaching maintains that chronic gastrointestinal ischemia occurs when two of the three major intestinal blood vessels have blocked blood flow; however, now many doctors believe that gastrointestinal ischemia may have a number of different causes including a neurologic component.
|
Causes of Median Arcuate Ligament Syndrome. The median arcuate ligament is formed by the merging of the right and left attachments of the diaphragm as they cross over the aorta as it enters the abdominal cavity from the chest. The relationship of the ligament to the celiac artery origin determines compression: when the celiac artery comes off the aorta above the diaphragm, this can result in compression; when the celiac artery branches off the aorta below the diaphragm, there is no compression. In a study of 75 autopsies, the median arcuate ligament crossed the celiac artery origin entirely (33%) or partially (48%) in a majority of individuals, resulting in significant celiac artery compression.1Since 13-50% of healthy asymptomatic patients have a form of celiac artery compression and a much smaller percentage of these patients actually report symptoms consistent with MALS,2 there is significant debate amongst doctors regarding the existence, the causes, and the management of MALS. The cause of the symptoms is thought to be due to either poor blood flow from celiac artery compression, nerve irritation from compression celiac nerve plexus, or a combination of both. Compression of the celiac artery may result in blood flow coming from another abdominal blood vessel (the superior mesenteric artery) and going to the stomach and liver when a patient eats. This is known as a “steal phenomenon” and a possible cause of abdominal pain.3-5 Another theory is that the nerves in the area of the celiac artery (the peri-aortic ganglia and celiac nerve plexus) are also thought to be overstimulated leading to spasm (vasoconstriction) of the arteries going to the stomach and small bowel and this results in symptoms. Another theory is the compression of the nerves causes interference of the brain/stomach (neuro-enteric) pain pathways resulting in hypersensitivity and pain in the stomach. Common surgical teaching maintains that chronic gastrointestinal ischemia occurs when two of the three major intestinal blood vessels have blocked blood flow; however, now many doctors believe that gastrointestinal ischemia may have a number of different causes including a neurologic component.
| 774 |
Median Arcuate Ligament Syndrome
|
nord_774_3
|
Affects of Median Arcuate Ligament Syndrome
|
The characteristic MALS patient is more likely to be young adult female, which is consistent with demographic characteristics of other chronic abdominal pain (CAP) patients. However, given the wide distribution of celiac artery compression, the syndrome affects both young and old as well as women and men.
|
Affects of Median Arcuate Ligament Syndrome. The characteristic MALS patient is more likely to be young adult female, which is consistent with demographic characteristics of other chronic abdominal pain (CAP) patients. However, given the wide distribution of celiac artery compression, the syndrome affects both young and old as well as women and men.
| 774 |
Median Arcuate Ligament Syndrome
|
nord_774_4
|
Related disorders of Median Arcuate Ligament Syndrome
|
The signs and symptoms of MALS are vague and overlap with a number of common and uncommon medical diagnoses (table 1).Table 1. Causes of upper abdominal chronic pain
Liver
hepatitis, Fitz-Hugh-Curtis syndrome, liver abscess, Budd-Chiari syndrome
Stomach
gastritis, peptic ulcer disease, gastro-esophageal reflux (GERD), gastroparesis, gluten allergy, foreign body, bezoar
Gastrointestinal
Crohn’s disease, inflammatory bowel disease, constipation, infection (colitis, or parasitic), malrotation, small intestinal bacterial overgrowth (SIBO), motility disorders
Pancreas
pancreatitis, pancreatic divisum, pancreatic cancer
Spleen
splenomegaly, splenic infarct, splenic abscess
Genitourinary
endometriosis, pregnancy, urinary tract infection, pelvic inflammatory disease, dysmenorrhea, pyelonephritis
Metabolic
carbohydrate malabsorbtion (lactose), heavy metal poisoning (lead), food sensitivities
Endocrine
hypothyroidism, hyperparathyroidism
Musculoskeletal
hernias, hematomas, cutaneous nerve entrapment, costochondritis, psoas abscess
Hematologic/Lymphatic
portal vein thrombosis, sickle-cell disease, malignancy, mesenteric lymphadenitis, porphyrias
Vascular
mesenteric ischemia, vasculitis, celiac artery compression
Psychiatric
eating disorders (anorexia nervosa, bulimia)
Similarly, the signs and symptoms of MALS overlap with a number of symptom-based (functional abdominal) diagnoses:The combination of upper abdominal pain and the finding of celiac artery compression on radiologic studies suggests the diagnosis of the MALS. The challenge with celiac artery compression is that a significant proportion of the population (13-50%) exhibit radiographic features of celiac artery compression, but do not demonstrate any symptoms. This has led to significant controversy regarding the existence and management of this syndrome.
|
Related disorders of Median Arcuate Ligament Syndrome. The signs and symptoms of MALS are vague and overlap with a number of common and uncommon medical diagnoses (table 1).Table 1. Causes of upper abdominal chronic pain
Liver
hepatitis, Fitz-Hugh-Curtis syndrome, liver abscess, Budd-Chiari syndrome
Stomach
gastritis, peptic ulcer disease, gastro-esophageal reflux (GERD), gastroparesis, gluten allergy, foreign body, bezoar
Gastrointestinal
Crohn’s disease, inflammatory bowel disease, constipation, infection (colitis, or parasitic), malrotation, small intestinal bacterial overgrowth (SIBO), motility disorders
Pancreas
pancreatitis, pancreatic divisum, pancreatic cancer
Spleen
splenomegaly, splenic infarct, splenic abscess
Genitourinary
endometriosis, pregnancy, urinary tract infection, pelvic inflammatory disease, dysmenorrhea, pyelonephritis
Metabolic
carbohydrate malabsorbtion (lactose), heavy metal poisoning (lead), food sensitivities
Endocrine
hypothyroidism, hyperparathyroidism
Musculoskeletal
hernias, hematomas, cutaneous nerve entrapment, costochondritis, psoas abscess
Hematologic/Lymphatic
portal vein thrombosis, sickle-cell disease, malignancy, mesenteric lymphadenitis, porphyrias
Vascular
mesenteric ischemia, vasculitis, celiac artery compression
Psychiatric
eating disorders (anorexia nervosa, bulimia)
Similarly, the signs and symptoms of MALS overlap with a number of symptom-based (functional abdominal) diagnoses:The combination of upper abdominal pain and the finding of celiac artery compression on radiologic studies suggests the diagnosis of the MALS. The challenge with celiac artery compression is that a significant proportion of the population (13-50%) exhibit radiographic features of celiac artery compression, but do not demonstrate any symptoms. This has led to significant controversy regarding the existence and management of this syndrome.
| 774 |
Median Arcuate Ligament Syndrome
|
nord_774_5
|
Diagnosis of Median Arcuate Ligament Syndrome
|
Because there are many patients with celiac artery compression and no symptoms, and because there are many causes for abdominal pain, it is important that patients are evaluated for all possible common causes of abdominal pain before being diagnosed with MALS. (Table 1)There has been very little published with specific protocols for diagnosis of MALS. Mak, et al reported the use of a specific diagnostic protocol. Complete medical evaluation should include blood work (complete blood count, chemistry panel, liver function tests, amylase, lipase, inflammation markers (erythrocyte sedimentation rate, C-reactive protein), pre-albumin, thyroid function tests), upper gastrointestinal imaging studies, small bowel follow-through, abdominal ultrasound, upper endoscopy with biopsy, and evaluation for inflammatory bowel disease and celiac disease. Patients are then screened with mesenteric duplex ultrasound. Positive findings demonstrate elevated blood flow velocities (PSV=peak systolic velocity) in the celiac artery greater than 200 cm/sec and an end diastolic velocity (EDV) greater than 55 cm/sec. Further demonstration of a decrease or even normalization of the velocities with deep inspiration is suggestive of celiac artery compression.4 Patients then undergo CT (computerized tomography) scan, MRA (magnetic resonance angiogram) or sometimes an angiogram to confirm the change in the shape of the celiac artery in both inspiratory and expiratory phases.4Once other common causes of pain have been excluded and celiac artery compression is confirmed, it is crucial that patients are evaluated for proper patient selection for surgical intervention. Patient characteristics reported to be predictive of successful outcomes following surgery include consistent abdominal pain after eating, patients between the ages of 40-60 years, and weight loss of 20 pounds or greater. Surgery tends to not help in patients in which the pain is atypical, there are periods of remission, in patients over the age of 60 years, in patients with a history of alcohol abuse, and weight loss of less than 20 pounds.4, 6-9Additionally, Mak et al reported incorporating psychiatric and chronic pain service in the pre-operative and post-operative evaluations given the correlation between chronic physical pain and psychological pain. Pre-operatively, all patients are evaluated by a multi-disciplinary team consisting of general and vascular surgery, psychiatry, and pain service. This team then discusses each patient, and surgery is not considered until the patient has been unanimously cleared by the entire team.4 We have found this approach to be extremely helpful to the patients.10-12
|
Diagnosis of Median Arcuate Ligament Syndrome. Because there are many patients with celiac artery compression and no symptoms, and because there are many causes for abdominal pain, it is important that patients are evaluated for all possible common causes of abdominal pain before being diagnosed with MALS. (Table 1)There has been very little published with specific protocols for diagnosis of MALS. Mak, et al reported the use of a specific diagnostic protocol. Complete medical evaluation should include blood work (complete blood count, chemistry panel, liver function tests, amylase, lipase, inflammation markers (erythrocyte sedimentation rate, C-reactive protein), pre-albumin, thyroid function tests), upper gastrointestinal imaging studies, small bowel follow-through, abdominal ultrasound, upper endoscopy with biopsy, and evaluation for inflammatory bowel disease and celiac disease. Patients are then screened with mesenteric duplex ultrasound. Positive findings demonstrate elevated blood flow velocities (PSV=peak systolic velocity) in the celiac artery greater than 200 cm/sec and an end diastolic velocity (EDV) greater than 55 cm/sec. Further demonstration of a decrease or even normalization of the velocities with deep inspiration is suggestive of celiac artery compression.4 Patients then undergo CT (computerized tomography) scan, MRA (magnetic resonance angiogram) or sometimes an angiogram to confirm the change in the shape of the celiac artery in both inspiratory and expiratory phases.4Once other common causes of pain have been excluded and celiac artery compression is confirmed, it is crucial that patients are evaluated for proper patient selection for surgical intervention. Patient characteristics reported to be predictive of successful outcomes following surgery include consistent abdominal pain after eating, patients between the ages of 40-60 years, and weight loss of 20 pounds or greater. Surgery tends to not help in patients in which the pain is atypical, there are periods of remission, in patients over the age of 60 years, in patients with a history of alcohol abuse, and weight loss of less than 20 pounds.4, 6-9Additionally, Mak et al reported incorporating psychiatric and chronic pain service in the pre-operative and post-operative evaluations given the correlation between chronic physical pain and psychological pain. Pre-operatively, all patients are evaluated by a multi-disciplinary team consisting of general and vascular surgery, psychiatry, and pain service. This team then discusses each patient, and surgery is not considered until the patient has been unanimously cleared by the entire team.4 We have found this approach to be extremely helpful to the patients.10-12
| 774 |
Median Arcuate Ligament Syndrome
|
nord_774_6
|
Therapies of Median Arcuate Ligament Syndrome
|
Treatment
The standard treatment of celiac artery compression syndrome is surgical release of the celiac artery from compression with simultaneous removal of the nerves that are being compressed as well. The different techniques for the surgical release of celiac artery compression consist of open, laparoscopic, and robotic procedures (all of which have been shown to be safe and effective) without any evidence to support one approach being better than the other. The general principles of the operation are: division of the median arcuate ligament including overlying lymphatics and soft tissue to relieve the compression of the celiac artery with or without division of the celiac nerve plexus. Some surgeons use ultrasound to verify adequate release while other surgeons determine adequate release by conformational change of the celiac artery. While there is debate regarding performance of celiac artery revascularization procedures concomitantly with the release or at a later date if symptoms recur, there is no reason to perform endovascular stenting of the celiac artery pre-operatively as these stents generally fail due to external compression from the median arcuate ligament.3, 5, 13, 14 One novel approach was described by van Petersen in which retroperitoneal endoscopic lysis of the median arcuate ligament was performed with similar safety and success rates.15Surgical Outcomes
Overall, reviews have found generally good outcomes following surgical treatment of MALS with the majority of studies showing improved post-operative abdominal pain. Average success rate of being symptom-free following surgical intervention is reported to be 60-80%.16, 17 However, optimal surgical outcomes are not universal. One of the few larger published series by Mak et al consists of 46 pediatric cases treated by laparoscopic release of the median arcuate ligament. The success rate was reported to be 83% with improved abdominal pain and quality of life. Post-operatively, a total of six patients required additional procedures due to persistent abdominal pain and nausea (two celiac plexus nerve blocks, two angiographies with angioplasties, one open aorto-celiac bypass, and one local block at previous umbilical port incision). Of these six patients, four still reported no improvement in abdominal pain. One of the limitations of this study was the poor compliance in completing the post-operative quality of life surveys. This improved later in the study but led to poor long-term follow-up data for the initial patients.4 The second large published series by van Petersen consisted of 46 patients who underwent retroperitoneal endoscopic release of the median arcuate ligament. They reported a success rate of 89% with 30 patients reporting no symptoms at follow-up and 11 patients reporting clear improvement of symptoms.15Post-operative complications tend to be minor and self-limited including diarrhea, nausea, and self-limited pancreatitis. The major post-operative problem is either continued or return of the abdominal pain. An important finding is that surgery does not treat any anxiety or depression that is also present.11, 12For those patients with recurrent or persistent abdominal pain, they are re-evaluated for possible re-narrowing of the celiac artery either due to formation of scar tissue in the artery wall (intravascular web) or the natural conformation of the celiac artery. These patients may require additional procedures typically with a balloon angioplasty. Additionally, there are some patients with recurrent or persistent abdominal that will now have normal blood flow. This suggests that they have chronic functional abdominal pain. Mak et al published a protocol for those patients with persistent symptoms. Repeat duplex ultrasound is first performed. Patients with significantly elevated velocities as well as continued respiratory variation then undergo angiography with possible angioplasty. In those patients with normalized celiac artery velocities, repeat CT angiogram is performed to evaluate for intra-abdominal pathology following surgery. If the CT is normal, patients are offered celiac plexus nerve block by anesthesia and are counseled that they may have functional abdominal pain.4Future
Significant controversy exists as to the true existence and the causes of this syndrome. Supporters of the syndrome attribute the symptoms to both poor blood flow (ischemia) from celiac artery compression as well as enlargement (hypertrophy) of the celiac nerve plexus and associated neuropathy. Histologic changes seen under the microscope (intimal hyperplasia, elastic fiber proliferation, and disorganization of the adventitia) in the arterial wall of the celiac artery have been described in patients with celiac artery compression as well.6 Classically, it was believed that pain of the intestine from poor blood flow (gastrointestinal ischemia) occurred when two of the three major intestinal vessels were involved; however, many physicians no longer support this notion and now believe that gastrointestinal ischemia is multifactorial in nature including a neurologic component.3, 5, 18 Opponents of MALS point to the natural finding of celiac artery compression in patients without any symptoms; additionally it is pointed out that symptoms don’t improve in all patients following surgery to treat MALS. All told, there are more factors than just compression of the celiac artery that need to be considered.11, 12, 19 Randomized controlled studies of patients diagnosed with celiac artery compression comparing non-operative management to surgery or placebo surgery to MALS release surgery would be beneficial to better delineate the effectiveness of surgery; however, there are ethical and patient perspective in the design of such trials that make them challenging. Patients seen in the clinic often request surgery as they are anxious for any possible solution due to the chronic pain. There is much opportunity to study the most effective management of these complex patients. It would also be useful to look at the patient characteristics or pre-operative evaluation that may predict success after surgical treatment as well as follow these patients for an extended period of time for long-term follow-up. Nonetheless, work needs to continue on unraveling this vexing cause of pain.
|
Therapies of Median Arcuate Ligament Syndrome. Treatment
The standard treatment of celiac artery compression syndrome is surgical release of the celiac artery from compression with simultaneous removal of the nerves that are being compressed as well. The different techniques for the surgical release of celiac artery compression consist of open, laparoscopic, and robotic procedures (all of which have been shown to be safe and effective) without any evidence to support one approach being better than the other. The general principles of the operation are: division of the median arcuate ligament including overlying lymphatics and soft tissue to relieve the compression of the celiac artery with or without division of the celiac nerve plexus. Some surgeons use ultrasound to verify adequate release while other surgeons determine adequate release by conformational change of the celiac artery. While there is debate regarding performance of celiac artery revascularization procedures concomitantly with the release or at a later date if symptoms recur, there is no reason to perform endovascular stenting of the celiac artery pre-operatively as these stents generally fail due to external compression from the median arcuate ligament.3, 5, 13, 14 One novel approach was described by van Petersen in which retroperitoneal endoscopic lysis of the median arcuate ligament was performed with similar safety and success rates.15Surgical Outcomes
Overall, reviews have found generally good outcomes following surgical treatment of MALS with the majority of studies showing improved post-operative abdominal pain. Average success rate of being symptom-free following surgical intervention is reported to be 60-80%.16, 17 However, optimal surgical outcomes are not universal. One of the few larger published series by Mak et al consists of 46 pediatric cases treated by laparoscopic release of the median arcuate ligament. The success rate was reported to be 83% with improved abdominal pain and quality of life. Post-operatively, a total of six patients required additional procedures due to persistent abdominal pain and nausea (two celiac plexus nerve blocks, two angiographies with angioplasties, one open aorto-celiac bypass, and one local block at previous umbilical port incision). Of these six patients, four still reported no improvement in abdominal pain. One of the limitations of this study was the poor compliance in completing the post-operative quality of life surveys. This improved later in the study but led to poor long-term follow-up data for the initial patients.4 The second large published series by van Petersen consisted of 46 patients who underwent retroperitoneal endoscopic release of the median arcuate ligament. They reported a success rate of 89% with 30 patients reporting no symptoms at follow-up and 11 patients reporting clear improvement of symptoms.15Post-operative complications tend to be minor and self-limited including diarrhea, nausea, and self-limited pancreatitis. The major post-operative problem is either continued or return of the abdominal pain. An important finding is that surgery does not treat any anxiety or depression that is also present.11, 12For those patients with recurrent or persistent abdominal pain, they are re-evaluated for possible re-narrowing of the celiac artery either due to formation of scar tissue in the artery wall (intravascular web) or the natural conformation of the celiac artery. These patients may require additional procedures typically with a balloon angioplasty. Additionally, there are some patients with recurrent or persistent abdominal that will now have normal blood flow. This suggests that they have chronic functional abdominal pain. Mak et al published a protocol for those patients with persistent symptoms. Repeat duplex ultrasound is first performed. Patients with significantly elevated velocities as well as continued respiratory variation then undergo angiography with possible angioplasty. In those patients with normalized celiac artery velocities, repeat CT angiogram is performed to evaluate for intra-abdominal pathology following surgery. If the CT is normal, patients are offered celiac plexus nerve block by anesthesia and are counseled that they may have functional abdominal pain.4Future
Significant controversy exists as to the true existence and the causes of this syndrome. Supporters of the syndrome attribute the symptoms to both poor blood flow (ischemia) from celiac artery compression as well as enlargement (hypertrophy) of the celiac nerve plexus and associated neuropathy. Histologic changes seen under the microscope (intimal hyperplasia, elastic fiber proliferation, and disorganization of the adventitia) in the arterial wall of the celiac artery have been described in patients with celiac artery compression as well.6 Classically, it was believed that pain of the intestine from poor blood flow (gastrointestinal ischemia) occurred when two of the three major intestinal vessels were involved; however, many physicians no longer support this notion and now believe that gastrointestinal ischemia is multifactorial in nature including a neurologic component.3, 5, 18 Opponents of MALS point to the natural finding of celiac artery compression in patients without any symptoms; additionally it is pointed out that symptoms don’t improve in all patients following surgery to treat MALS. All told, there are more factors than just compression of the celiac artery that need to be considered.11, 12, 19 Randomized controlled studies of patients diagnosed with celiac artery compression comparing non-operative management to surgery or placebo surgery to MALS release surgery would be beneficial to better delineate the effectiveness of surgery; however, there are ethical and patient perspective in the design of such trials that make them challenging. Patients seen in the clinic often request surgery as they are anxious for any possible solution due to the chronic pain. There is much opportunity to study the most effective management of these complex patients. It would also be useful to look at the patient characteristics or pre-operative evaluation that may predict success after surgical treatment as well as follow these patients for an extended period of time for long-term follow-up. Nonetheless, work needs to continue on unraveling this vexing cause of pain.
| 774 |
Median Arcuate Ligament Syndrome
|
nord_775_0
|
Overview of Medium Chain Acyl CoA Dehydrogenase Deficiency
|
SummaryMedium chain acyl-coA dehydrogenase deficiency (MCADD) is a genetic disorder caused by a lower than normal level of the medium chain acyl-coenzyme A dehydrogenase enzyme. This enzyme is involved in breaking down fat stores in the body to be used for energy. Symptoms of this disorder generally develop between 1 and 24 months of age, although they can sometimes first appear in adulthood. Individuals with MCADD experience symptoms of metabolic crisis due to low blood sugar (hypoglycemia) after periods of prolonged fasting or in response to a common illness. These may include weakness, vomiting, and seizures. Rarely, coma or sudden death may occur. MCADD is inherited as autosomal recessive genetic condition.IntroductionMCADD is usually diagnosed through newborn screening. An early diagnosis of this disorder is important in order to be able to prevent symptoms from occurring. Treatment involves avoiding long periods of fasting and restricting fat intake. MCADD is a known cause of sudden infant death syndrome (SIDS).
|
Overview of Medium Chain Acyl CoA Dehydrogenase Deficiency. SummaryMedium chain acyl-coA dehydrogenase deficiency (MCADD) is a genetic disorder caused by a lower than normal level of the medium chain acyl-coenzyme A dehydrogenase enzyme. This enzyme is involved in breaking down fat stores in the body to be used for energy. Symptoms of this disorder generally develop between 1 and 24 months of age, although they can sometimes first appear in adulthood. Individuals with MCADD experience symptoms of metabolic crisis due to low blood sugar (hypoglycemia) after periods of prolonged fasting or in response to a common illness. These may include weakness, vomiting, and seizures. Rarely, coma or sudden death may occur. MCADD is inherited as autosomal recessive genetic condition.IntroductionMCADD is usually diagnosed through newborn screening. An early diagnosis of this disorder is important in order to be able to prevent symptoms from occurring. Treatment involves avoiding long periods of fasting and restricting fat intake. MCADD is a known cause of sudden infant death syndrome (SIDS).
| 775 |
Medium Chain Acyl CoA Dehydrogenase Deficiency
|
nord_775_1
|
Symptoms of Medium Chain Acyl CoA Dehydrogenase Deficiency
|
Symptoms of MCADD are characterized by metabolic crisis brought about by low blood sugar (hypoglycemia). Because infants are typically weaned from nighttime feedings sometime between 3 and 24 months of age, this is when the infant’s first experience with longer fasting would occur. Being previously healthy, a child with MCADD might suddenly experience severe symptoms at this point. A child could also have symptoms in response to a common and normally mild disease like a cold, since it can decrease appetite and increase the body’s metabolic requirements. Alternatively, an individual with a milder form of MCADD might first develop symptoms in adulthood, in response to an extreme metabolic stress such as surgery or severe illness. A person with MCADD who never entered a low blood sugar state would never experience the symptoms of the disease.In the event of a hypoglycemic crisis, the affected individual might experience tiredness/weakness (lethargy), vomiting (emesis), seizures, coma, or sudden death (in 18% of first crises). Additional signs of the disease could include an enlarged liver (hepatomegaly), low blood sugar due to inefficient breakdown of fats (hypoketotic hypoglycemia), and elevated levels of certain substances in the blood or urine (e.g. acylglycines). Secondary symptoms of MCADD that can develop after a person has experienced one or multiple metabolic crises are caused by damage to body tissues due to the hypoglycemic conditions during the events. These can include lasting muscle weakness and pain, as well as reduced tolerance to exercise. Affected individuals may acquire such brain disorders as an inability to understand or use language (aphasia) and attention deficit disorder due to damage to the brain. Women with MCADD may experience pregnancy complications such as HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count).
|
Symptoms of Medium Chain Acyl CoA Dehydrogenase Deficiency. Symptoms of MCADD are characterized by metabolic crisis brought about by low blood sugar (hypoglycemia). Because infants are typically weaned from nighttime feedings sometime between 3 and 24 months of age, this is when the infant’s first experience with longer fasting would occur. Being previously healthy, a child with MCADD might suddenly experience severe symptoms at this point. A child could also have symptoms in response to a common and normally mild disease like a cold, since it can decrease appetite and increase the body’s metabolic requirements. Alternatively, an individual with a milder form of MCADD might first develop symptoms in adulthood, in response to an extreme metabolic stress such as surgery or severe illness. A person with MCADD who never entered a low blood sugar state would never experience the symptoms of the disease.In the event of a hypoglycemic crisis, the affected individual might experience tiredness/weakness (lethargy), vomiting (emesis), seizures, coma, or sudden death (in 18% of first crises). Additional signs of the disease could include an enlarged liver (hepatomegaly), low blood sugar due to inefficient breakdown of fats (hypoketotic hypoglycemia), and elevated levels of certain substances in the blood or urine (e.g. acylglycines). Secondary symptoms of MCADD that can develop after a person has experienced one or multiple metabolic crises are caused by damage to body tissues due to the hypoglycemic conditions during the events. These can include lasting muscle weakness and pain, as well as reduced tolerance to exercise. Affected individuals may acquire such brain disorders as an inability to understand or use language (aphasia) and attention deficit disorder due to damage to the brain. Women with MCADD may experience pregnancy complications such as HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count).
| 775 |
Medium Chain Acyl CoA Dehydrogenase Deficiency
|
nord_775_2
|
Causes of Medium Chain Acyl CoA Dehydrogenase Deficiency
|
MCADD is a genetic disorder of mitochondrial fatty acid beta-oxidation. This means that fats in the body cannot efficiently be broken down and used for energy. The body relies on glucose (a sugar) for energy, and during times when the amount of glucose in the blood is too low, the body can break down fat stores and convert them to glucose. Enzymes called acyl-coenzyme A dehydrogenases are necessary for one of the steps in the biochemical pathway by which fat is broken down into glucose. Medium chain acyl-coenzyme A dehydrogenase (MCAD) is one of these enzymes.In MCADD, the gene that codes for the MCAD enzyme (called ACADM) is altered, and too little functional MCAD enzyme is present in the body. This means that medium chained fats cannot be used effectively for energy once blood sugars drop. Since the body’s ability to replenish blood sugars is impaired, hypoglycemic symptoms can develop. Hypoglycemia is the direct cause of the symptoms of MCADD. However, precursor molecules and metabolites that become “stuck” in the biochemical pathway of fat breakdown due to deficient MCAD can build up in the body and cause some oxidative damage.MCADD is an autosomal recessive genetic condition. 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 Medium Chain Acyl CoA Dehydrogenase Deficiency. MCADD is a genetic disorder of mitochondrial fatty acid beta-oxidation. This means that fats in the body cannot efficiently be broken down and used for energy. The body relies on glucose (a sugar) for energy, and during times when the amount of glucose in the blood is too low, the body can break down fat stores and convert them to glucose. Enzymes called acyl-coenzyme A dehydrogenases are necessary for one of the steps in the biochemical pathway by which fat is broken down into glucose. Medium chain acyl-coenzyme A dehydrogenase (MCAD) is one of these enzymes.In MCADD, the gene that codes for the MCAD enzyme (called ACADM) is altered, and too little functional MCAD enzyme is present in the body. This means that medium chained fats cannot be used effectively for energy once blood sugars drop. Since the body’s ability to replenish blood sugars is impaired, hypoglycemic symptoms can develop. Hypoglycemia is the direct cause of the symptoms of MCADD. However, precursor molecules and metabolites that become “stuck” in the biochemical pathway of fat breakdown due to deficient MCAD can build up in the body and cause some oxidative damage.MCADD is an autosomal recessive genetic condition. 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.
| 775 |
Medium Chain Acyl CoA Dehydrogenase Deficiency
|
nord_775_3
|
Affects of Medium Chain Acyl CoA Dehydrogenase Deficiency
|
In the general population, MCADD occurs in approximately 1 in 50,000 individuals. The prevalence of MCADD in people of northern European descent has been estimated to be in the range of 1 in 6,400 to 1 in 46,000 individuals. Gypsies of Portugal and Native Americans of California also have a higher than average prevalence.
|
Affects of Medium Chain Acyl CoA Dehydrogenase Deficiency. In the general population, MCADD occurs in approximately 1 in 50,000 individuals. The prevalence of MCADD in people of northern European descent has been estimated to be in the range of 1 in 6,400 to 1 in 46,000 individuals. Gypsies of Portugal and Native Americans of California also have a higher than average prevalence.
| 775 |
Medium Chain Acyl CoA Dehydrogenase Deficiency
|
nord_775_4
|
Related disorders of Medium Chain Acyl CoA Dehydrogenase Deficiency
|
There are no other known disorders caused by abnormalities with the ACADM gene. However, MCADD is in a family of enzymes that are all important in the breakdown of fat for energy. For example, short-, long-, and very long- chain acyl-CoA dehydrogenases. It is possible of any one of these enzymes to be dysfunctional due to a defect in the gene that codes for it. Such a defect could lead to a disorder similar to MCADD, and collectively these are known as fatty acid oxidation disorders. Many such disorders involve symptoms that are similar to MCADD, but they tend to have their own specific symptoms that help to distinguish them. For example, in terms of MCADD-like symptoms, the addition of heart problems or lung issues would be more indicative of a deficiency in another type of enzyme, rather than MCADD. (For more information on such alternate disorders, choose “Acyl CoA Dehydrogenase” as your search term in the Rare Disease Database.)
|
Related disorders of Medium Chain Acyl CoA Dehydrogenase Deficiency. There are no other known disorders caused by abnormalities with the ACADM gene. However, MCADD is in a family of enzymes that are all important in the breakdown of fat for energy. For example, short-, long-, and very long- chain acyl-CoA dehydrogenases. It is possible of any one of these enzymes to be dysfunctional due to a defect in the gene that codes for it. Such a defect could lead to a disorder similar to MCADD, and collectively these are known as fatty acid oxidation disorders. Many such disorders involve symptoms that are similar to MCADD, but they tend to have their own specific symptoms that help to distinguish them. For example, in terms of MCADD-like symptoms, the addition of heart problems or lung issues would be more indicative of a deficiency in another type of enzyme, rather than MCADD. (For more information on such alternate disorders, choose “Acyl CoA Dehydrogenase” as your search term in the Rare Disease Database.)
| 775 |
Medium Chain Acyl CoA Dehydrogenase Deficiency
|
nord_775_5
|
Diagnosis of Medium Chain Acyl CoA Dehydrogenase Deficiency
|
MCADD is usually diagnosed through newborn screening by a blood test. The test looks for the amount of chemicals known as acylcarnitines. High levels of a type of acylcarnitine called octanoylcarnitine are characteristic of MCADD, but this is not specific to this disorder. Moreover, if an infant develops the classic symptoms or dies after being otherwise healthy, a diagnosis of MCADD would be considered. This means that vomiting, lethargy, and seizures after a period of fasting or a common illness in a previously healthy individual would suggest MCADD. Additionally, low blood sugar (hypoketonic hypoglycemia) in response to fasting or illness would be a more measurable sign of the disorder. It is also prudent to consider family genetic history when making a diagnosis. Some individuals may never develop symptoms of MCADD or be diagnosed.Clinical Testing/Workup
Various biochemical analyses can be used to further confirm the diagnosis of MCADD and to monitor the condition. Genetic testing to identify two copies of the pathogenic version (allele) of the ACADM gene may be done. It is possible to extract cells from the body, grow them in a culture dish, and run tests to directly assess the activity of MCAD or the cells’ ability to break down fat. Furthermore, urine analysis can be done to test for such metabolite markers as medium chain dicarboxylic acids or organic acids and acylglycines. Blood plasma tests to measure acylcarnitines like octanoylcarnitines (C8) may be done. In all cases, interpretation of these tests should take into consideration the symptomatic state of the person, as an asymptomatic individual may not show elevated levels of the various indicator molecules in the body. The results of the testing and confirmed diagnosis would provide valuable information for the genetic counseling of the individual’s family and any potential reproductive partner.
|
Diagnosis of Medium Chain Acyl CoA Dehydrogenase Deficiency. MCADD is usually diagnosed through newborn screening by a blood test. The test looks for the amount of chemicals known as acylcarnitines. High levels of a type of acylcarnitine called octanoylcarnitine are characteristic of MCADD, but this is not specific to this disorder. Moreover, if an infant develops the classic symptoms or dies after being otherwise healthy, a diagnosis of MCADD would be considered. This means that vomiting, lethargy, and seizures after a period of fasting or a common illness in a previously healthy individual would suggest MCADD. Additionally, low blood sugar (hypoketonic hypoglycemia) in response to fasting or illness would be a more measurable sign of the disorder. It is also prudent to consider family genetic history when making a diagnosis. Some individuals may never develop symptoms of MCADD or be diagnosed.Clinical Testing/Workup
Various biochemical analyses can be used to further confirm the diagnosis of MCADD and to monitor the condition. Genetic testing to identify two copies of the pathogenic version (allele) of the ACADM gene may be done. It is possible to extract cells from the body, grow them in a culture dish, and run tests to directly assess the activity of MCAD or the cells’ ability to break down fat. Furthermore, urine analysis can be done to test for such metabolite markers as medium chain dicarboxylic acids or organic acids and acylglycines. Blood plasma tests to measure acylcarnitines like octanoylcarnitines (C8) may be done. In all cases, interpretation of these tests should take into consideration the symptomatic state of the person, as an asymptomatic individual may not show elevated levels of the various indicator molecules in the body. The results of the testing and confirmed diagnosis would provide valuable information for the genetic counseling of the individual’s family and any potential reproductive partner.
| 775 |
Medium Chain Acyl CoA Dehydrogenase Deficiency
|
nord_775_6
|
Therapies of Medium Chain Acyl CoA Dehydrogenase Deficiency
|
TreatmentsThe focus of treatment for MCADD is the prevention of the symptoms. It is important to maintain blood sugar levels by avoiding fasting for long periods. Frequent feeding is encouraged, and it is helpful to consume sources of complex carbohydrates at bedtime in order to supply a steadier source of glucose overnight. Treatment requirements and recommendations will vary depending upon the severity of the deficiency—how much functional MCAD is present in the body. It is advisable to consult a genetic metabolic specialist and undergo routine surveillance of the condition. Because of the higher feeding requirements and lower tolerance of exercise associated with MCADD, it is also helpful to talk to a dietician in order to ensure one is consuming a healthful balanced diet, although significant dietary modification is generally not required. In general, feeding infants with formulas high in medium chain fatty acids is inadvisable. In adults, excessive alcohol consumption can lead to a metabolic crisis. In any case, a metabolic crisis can be treated or reverted by consuming a glucose supplement or foods high in sugars. Glucose can be administered directly to the blood (IV) as well.
|
Therapies of Medium Chain Acyl CoA Dehydrogenase Deficiency. TreatmentsThe focus of treatment for MCADD is the prevention of the symptoms. It is important to maintain blood sugar levels by avoiding fasting for long periods. Frequent feeding is encouraged, and it is helpful to consume sources of complex carbohydrates at bedtime in order to supply a steadier source of glucose overnight. Treatment requirements and recommendations will vary depending upon the severity of the deficiency—how much functional MCAD is present in the body. It is advisable to consult a genetic metabolic specialist and undergo routine surveillance of the condition. Because of the higher feeding requirements and lower tolerance of exercise associated with MCADD, it is also helpful to talk to a dietician in order to ensure one is consuming a healthful balanced diet, although significant dietary modification is generally not required. In general, feeding infants with formulas high in medium chain fatty acids is inadvisable. In adults, excessive alcohol consumption can lead to a metabolic crisis. In any case, a metabolic crisis can be treated or reverted by consuming a glucose supplement or foods high in sugars. Glucose can be administered directly to the blood (IV) as well.
| 775 |
Medium Chain Acyl CoA Dehydrogenase Deficiency
|
nord_776_0
|
Overview of Medullary Sponge Kidney
|
Medullary Sponge Kidney is a rare disorder characterized by the formation of cystic malformations in the collecting ducts and the tubular structures within the kidneys (tubules) that collect urine. One or both kidneys may be affected. The initial symptoms of this disorder may include blood in the urine (hematuria), calcium stone formation in the kidneys (nephrolithiasis) or infection. The exact cause of Medullary Sponge Kidney is not known.
|
Overview of Medullary Sponge Kidney. Medullary Sponge Kidney is a rare disorder characterized by the formation of cystic malformations in the collecting ducts and the tubular structures within the kidneys (tubules) that collect urine. One or both kidneys may be affected. The initial symptoms of this disorder may include blood in the urine (hematuria), calcium stone formation in the kidneys (nephrolithiasis) or infection. The exact cause of Medullary Sponge Kidney is not known.
| 776 |
Medullary Sponge Kidney
|
nord_776_1
|
Symptoms of Medullary Sponge Kidney
|
The first symptoms of Medullary Sponge Kidney typically blood in the urine, stone formation or signs of a urinary infection such as excessive urination (polyuria) and/or burning and pain while urinating. In some affected individuals, calcium stones may form in the kidneys (nephrolithiasis). These stones can cause low back pain in the area of the kidneys (renal colic) and pain in the lower back and lower abdomen. A prominent feature of Medullary Sponge Kidney is the excretion of small stones with the urinary flow. The passage of these stones can be profoundly painful. In a small number of cases, repeated urinary infections and damage to the kidneys may occur if stones become sufficiently large enough to block the flow of urine to the bladder (renal obstruction).The most common complication of Medullary Sponge Kidney involves the loss of the kidneys' capacity to concentrate waste products in the urine (filtration). This is due to the abnormal widening (dilatation) of the collecting tubes deep within the kidneys. Impaired filtration by the kidneys can result in the excessive accumulation of acidic waste products in the blood and body fluids (metabolic acidosis). Rare complications of Medullary Sponge Kidney may include severe damage to the kidneys (i.e., renal tubular acidosis) and kidney failure (i.e., end-stage renal disease).
|
Symptoms of Medullary Sponge Kidney. The first symptoms of Medullary Sponge Kidney typically blood in the urine, stone formation or signs of a urinary infection such as excessive urination (polyuria) and/or burning and pain while urinating. In some affected individuals, calcium stones may form in the kidneys (nephrolithiasis). These stones can cause low back pain in the area of the kidneys (renal colic) and pain in the lower back and lower abdomen. A prominent feature of Medullary Sponge Kidney is the excretion of small stones with the urinary flow. The passage of these stones can be profoundly painful. In a small number of cases, repeated urinary infections and damage to the kidneys may occur if stones become sufficiently large enough to block the flow of urine to the bladder (renal obstruction).The most common complication of Medullary Sponge Kidney involves the loss of the kidneys' capacity to concentrate waste products in the urine (filtration). This is due to the abnormal widening (dilatation) of the collecting tubes deep within the kidneys. Impaired filtration by the kidneys can result in the excessive accumulation of acidic waste products in the blood and body fluids (metabolic acidosis). Rare complications of Medullary Sponge Kidney may include severe damage to the kidneys (i.e., renal tubular acidosis) and kidney failure (i.e., end-stage renal disease).
| 776 |
Medullary Sponge Kidney
|
nord_776_2
|
Causes of Medullary Sponge Kidney
|
The exact cause of Medullary Sponge Kidney is not known and most cases occur sporadically for no apparent reason. Some cases are thought to run in families (familial) and may be inherited as an autosomal dominant genetic trait. However, this inheritance pattern has not been proven. Some studies have suggested there may be a a possible relationship between overactivity of the parathyroid gland (Hyperparathyroidism) and Medullary Sponge Kidney.
|
Causes of Medullary Sponge Kidney. The exact cause of Medullary Sponge Kidney is not known and most cases occur sporadically for no apparent reason. Some cases are thought to run in families (familial) and may be inherited as an autosomal dominant genetic trait. However, this inheritance pattern has not been proven. Some studies have suggested there may be a a possible relationship between overactivity of the parathyroid gland (Hyperparathyroidism) and Medullary Sponge Kidney.
| 776 |
Medullary Sponge Kidney
|
nord_776_3
|
Affects of Medullary Sponge Kidney
|
Medullary Sponge Kidney is a rare disorder that affects slightly more women than men. It is thought to occur in 1 in 1,000 to 5,000 people in the United States. Although the symptoms of Medullary Sponge Kidney may begin at any age, they usually develop during adolescence or in adults between the ages of 30 and 50 years. Approximately 13 percent of all people who develop kidney stones are eventually diagnosed with Medullary Sponge Kidney. Medullary Sponge Kidney may also develop in people with Beckwith-Wiedemann Syndrome. (For more information on Beckwith-Wiedemann Syndrome, see the related disorders section of this report.)
|
Affects of Medullary Sponge Kidney. Medullary Sponge Kidney is a rare disorder that affects slightly more women than men. It is thought to occur in 1 in 1,000 to 5,000 people in the United States. Although the symptoms of Medullary Sponge Kidney may begin at any age, they usually develop during adolescence or in adults between the ages of 30 and 50 years. Approximately 13 percent of all people who develop kidney stones are eventually diagnosed with Medullary Sponge Kidney. Medullary Sponge Kidney may also develop in people with Beckwith-Wiedemann Syndrome. (For more information on Beckwith-Wiedemann Syndrome, see the related disorders section of this report.)
| 776 |
Medullary Sponge Kidney
|
nord_776_4
|
Related disorders of Medullary Sponge Kidney
|
Related Disorders Symptoms of the following disorders can be similar to those of Medullary Sponge Kidney. Comparisons may be useful for a differential diagnosis:Medullary Sponge Kidney is associated with several developmental and genetic disorders including the following conditions. Comparisons may be useful for a differential diagnosis.Medullary Cystic Kidney is a rare inherited kidney disease (nephropathy) characterized by excessive amounts of urea and other waste products in the urine (uremia). Impairment of kidney function occurs due to the development of numerous cysts deep within the kidneys (medulla). In most cases, the first symptoms of this disorder appear during childhood or adolescence (Familial Juvenile Nephronophthisis). People with Medullary Cystic Kidney Disease typically pass large volumes of urine (polyuria) that contain abnormally high levels of salt (sodium-wasting). Other symptoms may include excessive thirst (polydipsia), general weakness, lack of normal color in the face (pallor), and the inability to control bladder function (incontinence), especially during the night. (For more information on this disorder, choose “Medullary Cystic” as your search term in the Rare Disease Database.)Polycystic Kidney Disease is an inherited disorder characterized by the presence of cysts in both kidneys (bilateral renal disease). Progressive enlargement of these cysts causes the loss of normal kidney function and an abnormal increase in the vascular blood pressure around the kidneys (renal hypertension). There are infantile and adult forms of Polycystic Kidney Disease. Symptoms may include abdominal enlargement, back pain, weight loss, and/or unusually low levels of fluid in the body (dehydration). Some people with this disorder may also have liver problems and abnormal enlargement of the spleen (splenomegaly). (For more information on this disorder, choose “Polycystic Kidney” as your search term in the Rare Disease Database.)Beckwith-Wiedemann Syndrome is a rare congenital disorder characterized by an abnormally enlarged tongue (macroglossia), an opening in the abdominal wall through which the organs of the abdomen may protrude (omphalocele), excessive size and height (macrosomia), and unusual ear creases. Although some children with this disorder have few or no symptoms, a variety of symptoms are possible. Other symptoms may include abnormally low blood sugar (hypoglycemia), mental retardation, an abnormal increase in the number of red blood cells (polycythemia), and an unusually small head (microcephaly). Some children with Beckwith-Wiedemann Syndrome may develop Medullary Sponge Kidneys and/or malignant tumors of the kidneys. (For more information on this disorder, choose “Beckwith-Wiedemann” as your search term in the Rare Disease Database.)Caroli Disease is a rare inherited disorder characterized by abnormal widening (dilatation) of the ducts that carry bile from the liver (intrahepatic bile ducts). According to the medical literature, there are two forms of Caroli Disease. In most cases of the isolated or simple form of Caroli Disease, affected individuals experience recurrent episodes of inflammation of the bile ducts (cholangitis) and unusual accumulation of pus (abscesses) on the liver. A second form of Caroli Disease is associated with abnormal formation of bands of fibrous tissue in the portal area of the liver (congenital hepatic fibrosis). This form of Caroli Disease is also often associated with high blood pressure of the portal vein (portal hypertension), polycystic kidney disease, and, in severe cases, liver failure. Caroli Disease is thought to be inherited as either an autosomal dominant or recessive genetic trait. (For more information on this disorder, choose “Caroli Disease” as your search in the Rare Disease Database.)Ehlers-Danlos syndrome (EDS) is a group of hereditary connective tissue disorders characterized by defects of the major structural protein in the body (collagen). Collagen, a tough, fibrous protein, plays an essential role in holding together, strengthening, and providing elasticity to bodily cells and tissues. Due to defects of collagen, primary EDS symptoms and findings include abnormally flexible, loose joints (articular hypermobility) that may easily become dislocated; unusually loose, thin, stretchy (elastic) skin; and excessive fragility of the skin, blood vessels, and other bodily tissues and membranes. (For more information on this disorder, choose “Ehlers-Danlos Syndrome” as your search term in the Rare Disease Database.) Marfan syndrome is an inherited disorder that affects the connective tissue of the heart and blood vessels (cardiovascular system). The musculoskeletal system (ligaments and muscles) and ocular system (eyes) are also affected. Major symptoms also include unusual height, large hands and feet, and involvement of the lungs. (For more information on this disorder, choose “Marfan Syndrome” as your search term in the Rare Disease Database.)
|
Related disorders of Medullary Sponge Kidney. Related Disorders Symptoms of the following disorders can be similar to those of Medullary Sponge Kidney. Comparisons may be useful for a differential diagnosis:Medullary Sponge Kidney is associated with several developmental and genetic disorders including the following conditions. Comparisons may be useful for a differential diagnosis.Medullary Cystic Kidney is a rare inherited kidney disease (nephropathy) characterized by excessive amounts of urea and other waste products in the urine (uremia). Impairment of kidney function occurs due to the development of numerous cysts deep within the kidneys (medulla). In most cases, the first symptoms of this disorder appear during childhood or adolescence (Familial Juvenile Nephronophthisis). People with Medullary Cystic Kidney Disease typically pass large volumes of urine (polyuria) that contain abnormally high levels of salt (sodium-wasting). Other symptoms may include excessive thirst (polydipsia), general weakness, lack of normal color in the face (pallor), and the inability to control bladder function (incontinence), especially during the night. (For more information on this disorder, choose “Medullary Cystic” as your search term in the Rare Disease Database.)Polycystic Kidney Disease is an inherited disorder characterized by the presence of cysts in both kidneys (bilateral renal disease). Progressive enlargement of these cysts causes the loss of normal kidney function and an abnormal increase in the vascular blood pressure around the kidneys (renal hypertension). There are infantile and adult forms of Polycystic Kidney Disease. Symptoms may include abdominal enlargement, back pain, weight loss, and/or unusually low levels of fluid in the body (dehydration). Some people with this disorder may also have liver problems and abnormal enlargement of the spleen (splenomegaly). (For more information on this disorder, choose “Polycystic Kidney” as your search term in the Rare Disease Database.)Beckwith-Wiedemann Syndrome is a rare congenital disorder characterized by an abnormally enlarged tongue (macroglossia), an opening in the abdominal wall through which the organs of the abdomen may protrude (omphalocele), excessive size and height (macrosomia), and unusual ear creases. Although some children with this disorder have few or no symptoms, a variety of symptoms are possible. Other symptoms may include abnormally low blood sugar (hypoglycemia), mental retardation, an abnormal increase in the number of red blood cells (polycythemia), and an unusually small head (microcephaly). Some children with Beckwith-Wiedemann Syndrome may develop Medullary Sponge Kidneys and/or malignant tumors of the kidneys. (For more information on this disorder, choose “Beckwith-Wiedemann” as your search term in the Rare Disease Database.)Caroli Disease is a rare inherited disorder characterized by abnormal widening (dilatation) of the ducts that carry bile from the liver (intrahepatic bile ducts). According to the medical literature, there are two forms of Caroli Disease. In most cases of the isolated or simple form of Caroli Disease, affected individuals experience recurrent episodes of inflammation of the bile ducts (cholangitis) and unusual accumulation of pus (abscesses) on the liver. A second form of Caroli Disease is associated with abnormal formation of bands of fibrous tissue in the portal area of the liver (congenital hepatic fibrosis). This form of Caroli Disease is also often associated with high blood pressure of the portal vein (portal hypertension), polycystic kidney disease, and, in severe cases, liver failure. Caroli Disease is thought to be inherited as either an autosomal dominant or recessive genetic trait. (For more information on this disorder, choose “Caroli Disease” as your search in the Rare Disease Database.)Ehlers-Danlos syndrome (EDS) is a group of hereditary connective tissue disorders characterized by defects of the major structural protein in the body (collagen). Collagen, a tough, fibrous protein, plays an essential role in holding together, strengthening, and providing elasticity to bodily cells and tissues. Due to defects of collagen, primary EDS symptoms and findings include abnormally flexible, loose joints (articular hypermobility) that may easily become dislocated; unusually loose, thin, stretchy (elastic) skin; and excessive fragility of the skin, blood vessels, and other bodily tissues and membranes. (For more information on this disorder, choose “Ehlers-Danlos Syndrome” as your search term in the Rare Disease Database.) Marfan syndrome is an inherited disorder that affects the connective tissue of the heart and blood vessels (cardiovascular system). The musculoskeletal system (ligaments and muscles) and ocular system (eyes) are also affected. Major symptoms also include unusual height, large hands and feet, and involvement of the lungs. (For more information on this disorder, choose “Marfan Syndrome” as your search term in the Rare Disease Database.)
| 776 |
Medullary Sponge Kidney
|
nord_776_5
|
Diagnosis of Medullary Sponge Kidney
|
Diagnosis of Medullary Sponge Kidney.
| 776 |
Medullary Sponge Kidney
|
|
nord_776_6
|
Therapies of Medullary Sponge Kidney
|
The diagnosis of Medullary Sponge Kidney Disease may be confirmed by a thorough clinical evaluation and specialized X-ray studies (i.e., intravenous urography) that reveal the presence of abnormal widening (dilatation) or stretching of collecting ducts, cyst formations or kidney stones. CT scan (computerized tomography) is another imaging study that is effective in revealing calcifications that may later form kidney stones. In some affected individuals, urinary filtration rates (glomerular) may be measured and found to be reduced.The kidney stones associated with Medullary Sponge Kidney are composed of calcium oxalate, calcium phosphate, and other calcium salts (urolithiasis). If normal levels of calcium are excreted, affected individuals may be given oral phosphate therapy. Individuals with Medullary Sponge Kidney should take sufficient fluids in order to excrete about 2 liters of urine each day. Those people with Medullary Sponge Kidney who have too much calcium in their urine (hypercalciuria) may benefit from long-term therapy with thiazide diuretics as well as a high fluid intake.In some people with Medullary Sponge Kidney, a low calcium diet may help t. prevent the formation of kidney stones and thereby reduce the complications of urinary obstruction. Patients should be evaluated at least on a yearly basis, including routine urinalysis and urine cultures. Many patients with Medullary Sponge Kidney have recurrent urinary tract infections and may require antibiotic drugs to help prevent future infections (prophylaxis).Stones in the collecting system may be treated with electromagnetic shock waves (extracorporeal shock wave lithotripsy [ESWL]). During this procedure, the patient is placed in a large tub of water and shock waves (high energy) are delivered by a special machine (ellipsoid reflector) directly to the area of the kidney stones. The stones are broken into small pieces and excreted with the urine. It has not been determined if ESWL is beneficial in treating stones in the kidney tubules.Genetic counseling may be of benefit for people with Medullary Sponge Kidney if the disease appears in other family members. In rare cases of kidney failure, renal dialysis may be required. Other treatment is symptomatic and supportive.
|
Therapies of Medullary Sponge Kidney. The diagnosis of Medullary Sponge Kidney Disease may be confirmed by a thorough clinical evaluation and specialized X-ray studies (i.e., intravenous urography) that reveal the presence of abnormal widening (dilatation) or stretching of collecting ducts, cyst formations or kidney stones. CT scan (computerized tomography) is another imaging study that is effective in revealing calcifications that may later form kidney stones. In some affected individuals, urinary filtration rates (glomerular) may be measured and found to be reduced.The kidney stones associated with Medullary Sponge Kidney are composed of calcium oxalate, calcium phosphate, and other calcium salts (urolithiasis). If normal levels of calcium are excreted, affected individuals may be given oral phosphate therapy. Individuals with Medullary Sponge Kidney should take sufficient fluids in order to excrete about 2 liters of urine each day. Those people with Medullary Sponge Kidney who have too much calcium in their urine (hypercalciuria) may benefit from long-term therapy with thiazide diuretics as well as a high fluid intake.In some people with Medullary Sponge Kidney, a low calcium diet may help t. prevent the formation of kidney stones and thereby reduce the complications of urinary obstruction. Patients should be evaluated at least on a yearly basis, including routine urinalysis and urine cultures. Many patients with Medullary Sponge Kidney have recurrent urinary tract infections and may require antibiotic drugs to help prevent future infections (prophylaxis).Stones in the collecting system may be treated with electromagnetic shock waves (extracorporeal shock wave lithotripsy [ESWL]). During this procedure, the patient is placed in a large tub of water and shock waves (high energy) are delivered by a special machine (ellipsoid reflector) directly to the area of the kidney stones. The stones are broken into small pieces and excreted with the urine. It has not been determined if ESWL is beneficial in treating stones in the kidney tubules.Genetic counseling may be of benefit for people with Medullary Sponge Kidney if the disease appears in other family members. In rare cases of kidney failure, renal dialysis may be required. Other treatment is symptomatic and supportive.
| 776 |
Medullary Sponge Kidney
|
nord_777_0
|
Overview of Medulloblastoma
|
Medulloblastoma is the most common malignant brain tumor in children. Medulloblastomas by definition occur in the cerebellum, which is the part of brain located at the base of the skull, just above the brainstem. The cerebellum is involved in many functions including coordination of voluntary movements (e.g., walking, fine motor skills) and regulating balance and posture. Medulloblastomas arise from primitive, undeveloped cells in the brain. Most medulloblastomas occur in infants and children. Less commonly, these tumors can develop in adults as well. Symptoms associated with a medulloblastoma include headaches in the morning that improve as the day goes on, recurrent vomiting and difficulty walking and with balance. Medulloblastomas can spread to other areas of the central nervous system. The exact cause of a medulloblastoma is unknown.
|
Overview of Medulloblastoma. Medulloblastoma is the most common malignant brain tumor in children. Medulloblastomas by definition occur in the cerebellum, which is the part of brain located at the base of the skull, just above the brainstem. The cerebellum is involved in many functions including coordination of voluntary movements (e.g., walking, fine motor skills) and regulating balance and posture. Medulloblastomas arise from primitive, undeveloped cells in the brain. Most medulloblastomas occur in infants and children. Less commonly, these tumors can develop in adults as well. Symptoms associated with a medulloblastoma include headaches in the morning that improve as the day goes on, recurrent vomiting and difficulty walking and with balance. Medulloblastomas can spread to other areas of the central nervous system. The exact cause of a medulloblastoma is unknown.
| 777 |
Medulloblastoma
|
nord_777_1
|
Symptoms of Medulloblastoma
|
The specific symptoms associated with a medulloblastoma will vary from one person to another based upon the exact location and size of a medulloblastoma and whether the tumor has spread to other areas. Affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The symptoms of medulloblastoma usually result from increased pressure within the skull (intracranial pressure). Medulloblastomas generally arise in or near the base of the skull, an area known as the posterior fossa. The posterior fossa contains the brainstem and the cerebellum. Medulloblastomas typically involve the fluid-filled fourth cavity (ventricle) of the brain. The brain has four cavities called ventricles that are filled with cerebrospinal fluid (CSF) and joined by channels, through which CSF circulates. Because the tumor often fills the fourth ventricle, CSF circulation is obstructed, resulting in hydrocephalus. Hydrocephalus is a condition in which the accumulation of excess CSF in the brain causes a variety of symptoms, including repeated, often severe vomiting, lethargy and headaches that frequently occur in the morning and improve as the day goes on. Additional symptoms may include irritability, increased head size, and paralysis (paresis) of the muscles that help control eye movements (extraocular muscles).Many infants and children with a medulloblastoma develop papilledema, a condition in which the optic nerve swells because of increased intracranial pressure. The optic nerve is the nerve that transmits impulses from the retina to the brain. Papilledema can cause reduced clarity of vision. Because many the symptoms associated with a medulloblastoma are nonspecific and often subtle, papilledema may the first sign that brings affected infants and children to the attention of a neurologist. Children with medulloblastoma often have evidence of cerebellar dysfunction. Symptoms may include poor coordination, difficulty walking, and clumsiness (ataxia). Affected children may fall frequently and develop an unsteady, clumsy manner of walking (unsteady gait). They may tend to stand with their feet widely separated, stagger or sway when walking and easily lose their balance. As a tumor grows or spreads, additional symptoms can develop. Such symptoms may include double vision (diplopia), rapid, jerky movements of the eyes (nystagmus), facial weakness, ringing in the ears (tinnitus), hearing loss and a stiff neck. Some children with double vision may tilt their heads in an effort align the two images.
|
Symptoms of Medulloblastoma. The specific symptoms associated with a medulloblastoma will vary from one person to another based upon the exact location and size of a medulloblastoma and whether the tumor has spread to other areas. Affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.The symptoms of medulloblastoma usually result from increased pressure within the skull (intracranial pressure). Medulloblastomas generally arise in or near the base of the skull, an area known as the posterior fossa. The posterior fossa contains the brainstem and the cerebellum. Medulloblastomas typically involve the fluid-filled fourth cavity (ventricle) of the brain. The brain has four cavities called ventricles that are filled with cerebrospinal fluid (CSF) and joined by channels, through which CSF circulates. Because the tumor often fills the fourth ventricle, CSF circulation is obstructed, resulting in hydrocephalus. Hydrocephalus is a condition in which the accumulation of excess CSF in the brain causes a variety of symptoms, including repeated, often severe vomiting, lethargy and headaches that frequently occur in the morning and improve as the day goes on. Additional symptoms may include irritability, increased head size, and paralysis (paresis) of the muscles that help control eye movements (extraocular muscles).Many infants and children with a medulloblastoma develop papilledema, a condition in which the optic nerve swells because of increased intracranial pressure. The optic nerve is the nerve that transmits impulses from the retina to the brain. Papilledema can cause reduced clarity of vision. Because many the symptoms associated with a medulloblastoma are nonspecific and often subtle, papilledema may the first sign that brings affected infants and children to the attention of a neurologist. Children with medulloblastoma often have evidence of cerebellar dysfunction. Symptoms may include poor coordination, difficulty walking, and clumsiness (ataxia). Affected children may fall frequently and develop an unsteady, clumsy manner of walking (unsteady gait). They may tend to stand with their feet widely separated, stagger or sway when walking and easily lose their balance. As a tumor grows or spreads, additional symptoms can develop. Such symptoms may include double vision (diplopia), rapid, jerky movements of the eyes (nystagmus), facial weakness, ringing in the ears (tinnitus), hearing loss and a stiff neck. Some children with double vision may tilt their heads in an effort align the two images.
| 777 |
Medulloblastoma
|
nord_777_2
|
Causes of Medulloblastoma
|
The exact underlying cause of medulloblastoma is unknown. Most cases occur randomly for no apparent reason (sporadically). Many cases of medulloblastoma are associated with chromosomal abnormalities. These abnormalities are not inherited (i.e., are not passed on from one generation to the next), but occur at some unknown point during a child's development, even during the development of a fetus or embryo. Although medulloblastomas are associated with chromosomal changes, they are not inherited. In individuals with cancer, malignancies may develop due to abnormal changes in the structure and orientation of certain cells. As mentioned above, the specific cause or causes of such changes are unknown. However, research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body's genetic code, are the underlying basis of cellular malignant transformation. Depending upon the form of cancer present and several other factors, these abnormal genetic changes may occur spontaneously for unknown reasons (sporadically). Evidence suggests that, in approximately one-third to one-half of individuals with a medulloblastoma, tumor cells may have a specific chromosomal abnormality, known as isochromosome 17q, with associated loss or inactivation of certain genetic information. Chromosomes, which are present in the nucleus of human cells, carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” a long arm identified by the letter “q” and a narrowed region at which the two arms are joined (centromere). An isochromosome is an abnormal chromosome with identical arms on each side of the centromere. More specifically, in certain cases of medulloblastoma, there is duplication of the long arm and deletion of the short arm of chromosome 17. Some researchers suggest that such structural abnormalities of chromosome 17 may lead to inactivation of a gene on the chromosome that normally acts as a tumor suppressor, potentially leading to malignant transformation of certain cells. However, the implications of such findings remain unclear. Additional chromosomal abnormalities have been identified in individuals with medulloblastoma including abnormalities on chromosome 1, 7, 8, 9, 10q, 11, and 16. How these various abnormalities play a role in the development of medulloblastoma is unknown. Further research is needed to determine the complex underlying mechanisms responsible for the development of a medulloblastoma. In individuals with cancer, including medulloblastoma, malignancies may develop due to abnormal changes in the structure and orientation of certain cells known as oncogenes or tumor suppressor genes. Oncogenes control cell growth; tumor suppressor genes control cell division and ensure that cells die at the proper time. Oncogenes that are associated with medulloblastoma include ERBB2, MYCC, and OTX2. Many medulloblastomas are characterized by alterations in specific molecular signaling pathways that result in uncontrolled cell growth. Pathways implicated in medulloblastoma include the Wnt pathway, the SHH pathway and the myc pathway. In extremely rare cases, medulloblastomas occur in individuals who have certain inherited disorders including Gorlin syndrome (nevoid basal cell carcinoma), Turcot syndrome, Li Fraumeni syndrome, Rubinsten-Taybi syndrome, Nijmegen breakage syndrome, neurofibromatosis and ataxia-telangiectasia. Individuals with these disorders have an increased risk of developing a medulloblastoma. (For more information on these disorders, choose the specific disorder name in the Rare Disease Database.) Researchers theorize that medulloblastoma originates from immature cells that are somehow prevented from maturing (i.e., differentiating) into more specialized cells, which have “intended”, specific functions within the tissue in question. Such immature or incompletely differentiated cells may grow and divide at an unusually rapid, uncontrolled rate that cannot be contained by the body's natural immune defenses. Eventually, such proliferation of abnormal cells may result in formation of a mass known as a tumor (neoplasm). Several different subtypes of medulloblastoma have been identified including anaplastic (large cell) medulloblastoma; classic medulloblastoma; desmoplastic nodular medulloblastoma; medulloblastoma with extensive nodularity (MBEN); medullomyoblastoma; and melanotic medulloblastoma. The various subtypes of medulloblastoma appear different on a cellular level, but as yet to not influence treatment options. However, in the future such distinctions may be used to develop novel, targeted therapies based on a particular subtype and other factors.Extensive transcriptional profiling of human medulloblastomas has recently yielded a second and more precise classification system that stratifies medulloblastomas according to their mRNA expression profiles. Four subgroups with distinct mRNA signatures have been identified, and are presently categorized as WNT, Sonic hedgehog (SHH), Group 3 and Group 4.Medulloblastomas in the WNT subgroup feature genetic alterations that affect members of the Wnt signaling pathway, which are linked to the processes of embryogenesis and oncogenesis. Mutations of the ß-catenin gene and monosomy 6 are among the more common genetic events that define this subgroup, and the incidence rate among males and females is approximately equal. WNT subgroup medulloblastomas tend to affect older children and are rare in adults. Among the different subgroups, WNT tumors have the best prognosis and clinical outcomes. The SHH subgroup is characterized by up-regulation of members of the SHH signaling family. Common genetic events exclusive to this subgroup are mutations in the genes for PTCH, the receptor of SHH, and SUFU, a negative regulator of SHH signaling pathway. SHH tumors are the most common subgroup of medulloblastoma found in infants and adults, and they carry an intermediate prognosis. Like the WNT subgroup, the incidence of SHH tumors is equal for males and females. Group 3 tumors are characterized by over-amplification of MYC and genes related to phototransduction and glutamate signaling. These tumors are also known for their high frequency of metastasis and have the worst prognosis of any medulloblastoma subtype. Group 3 tumors are extremely rare in adults, and are more prevalent in males than females. The last subgroup, currently known as Group 4, is characterized by up-regulation of genes related to neuronal or glutameminergic signaling. Although these tumors are common across all age groups, comparatively little is known about them. Like Group 3, Group 4 tumors are more prevalent in males and have a high tendency to metastasize. Their prognosis is considered intermediate.Medulloblastoma is sometimes classified as a primitive neuroectodermal tumor or PNET. PNETs are a group of tumors that arise from primitive nerve cells in the brain. A medulloblastoma is sometimes referred to as a primitive neuroectodermal tumor of the posterior fossa.
|
Causes of Medulloblastoma. The exact underlying cause of medulloblastoma is unknown. Most cases occur randomly for no apparent reason (sporadically). Many cases of medulloblastoma are associated with chromosomal abnormalities. These abnormalities are not inherited (i.e., are not passed on from one generation to the next), but occur at some unknown point during a child's development, even during the development of a fetus or embryo. Although medulloblastomas are associated with chromosomal changes, they are not inherited. In individuals with cancer, malignancies may develop due to abnormal changes in the structure and orientation of certain cells. As mentioned above, the specific cause or causes of such changes are unknown. However, research suggests that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body's genetic code, are the underlying basis of cellular malignant transformation. Depending upon the form of cancer present and several other factors, these abnormal genetic changes may occur spontaneously for unknown reasons (sporadically). Evidence suggests that, in approximately one-third to one-half of individuals with a medulloblastoma, tumor cells may have a specific chromosomal abnormality, known as isochromosome 17q, with associated loss or inactivation of certain genetic information. Chromosomes, which are present in the nucleus of human cells, carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” a long arm identified by the letter “q” and a narrowed region at which the two arms are joined (centromere). An isochromosome is an abnormal chromosome with identical arms on each side of the centromere. More specifically, in certain cases of medulloblastoma, there is duplication of the long arm and deletion of the short arm of chromosome 17. Some researchers suggest that such structural abnormalities of chromosome 17 may lead to inactivation of a gene on the chromosome that normally acts as a tumor suppressor, potentially leading to malignant transformation of certain cells. However, the implications of such findings remain unclear. Additional chromosomal abnormalities have been identified in individuals with medulloblastoma including abnormalities on chromosome 1, 7, 8, 9, 10q, 11, and 16. How these various abnormalities play a role in the development of medulloblastoma is unknown. Further research is needed to determine the complex underlying mechanisms responsible for the development of a medulloblastoma. In individuals with cancer, including medulloblastoma, malignancies may develop due to abnormal changes in the structure and orientation of certain cells known as oncogenes or tumor suppressor genes. Oncogenes control cell growth; tumor suppressor genes control cell division and ensure that cells die at the proper time. Oncogenes that are associated with medulloblastoma include ERBB2, MYCC, and OTX2. Many medulloblastomas are characterized by alterations in specific molecular signaling pathways that result in uncontrolled cell growth. Pathways implicated in medulloblastoma include the Wnt pathway, the SHH pathway and the myc pathway. In extremely rare cases, medulloblastomas occur in individuals who have certain inherited disorders including Gorlin syndrome (nevoid basal cell carcinoma), Turcot syndrome, Li Fraumeni syndrome, Rubinsten-Taybi syndrome, Nijmegen breakage syndrome, neurofibromatosis and ataxia-telangiectasia. Individuals with these disorders have an increased risk of developing a medulloblastoma. (For more information on these disorders, choose the specific disorder name in the Rare Disease Database.) Researchers theorize that medulloblastoma originates from immature cells that are somehow prevented from maturing (i.e., differentiating) into more specialized cells, which have “intended”, specific functions within the tissue in question. Such immature or incompletely differentiated cells may grow and divide at an unusually rapid, uncontrolled rate that cannot be contained by the body's natural immune defenses. Eventually, such proliferation of abnormal cells may result in formation of a mass known as a tumor (neoplasm). Several different subtypes of medulloblastoma have been identified including anaplastic (large cell) medulloblastoma; classic medulloblastoma; desmoplastic nodular medulloblastoma; medulloblastoma with extensive nodularity (MBEN); medullomyoblastoma; and melanotic medulloblastoma. The various subtypes of medulloblastoma appear different on a cellular level, but as yet to not influence treatment options. However, in the future such distinctions may be used to develop novel, targeted therapies based on a particular subtype and other factors.Extensive transcriptional profiling of human medulloblastomas has recently yielded a second and more precise classification system that stratifies medulloblastomas according to their mRNA expression profiles. Four subgroups with distinct mRNA signatures have been identified, and are presently categorized as WNT, Sonic hedgehog (SHH), Group 3 and Group 4.Medulloblastomas in the WNT subgroup feature genetic alterations that affect members of the Wnt signaling pathway, which are linked to the processes of embryogenesis and oncogenesis. Mutations of the ß-catenin gene and monosomy 6 are among the more common genetic events that define this subgroup, and the incidence rate among males and females is approximately equal. WNT subgroup medulloblastomas tend to affect older children and are rare in adults. Among the different subgroups, WNT tumors have the best prognosis and clinical outcomes. The SHH subgroup is characterized by up-regulation of members of the SHH signaling family. Common genetic events exclusive to this subgroup are mutations in the genes for PTCH, the receptor of SHH, and SUFU, a negative regulator of SHH signaling pathway. SHH tumors are the most common subgroup of medulloblastoma found in infants and adults, and they carry an intermediate prognosis. Like the WNT subgroup, the incidence of SHH tumors is equal for males and females. Group 3 tumors are characterized by over-amplification of MYC and genes related to phototransduction and glutamate signaling. These tumors are also known for their high frequency of metastasis and have the worst prognosis of any medulloblastoma subtype. Group 3 tumors are extremely rare in adults, and are more prevalent in males than females. The last subgroup, currently known as Group 4, is characterized by up-regulation of genes related to neuronal or glutameminergic signaling. Although these tumors are common across all age groups, comparatively little is known about them. Like Group 3, Group 4 tumors are more prevalent in males and have a high tendency to metastasize. Their prognosis is considered intermediate.Medulloblastoma is sometimes classified as a primitive neuroectodermal tumor or PNET. PNETs are a group of tumors that arise from primitive nerve cells in the brain. A medulloblastoma is sometimes referred to as a primitive neuroectodermal tumor of the posterior fossa.
| 777 |
Medulloblastoma
|
nord_777_3
|
Affects of Medulloblastoma
|
Medulloblastomas can affect individuals of any age, but occur most often in children under the age of 15 with a peak incidence between 3 and 9 years of age. Medulloblastomas are the most common malignant brain tumor in children. Approximately 80 percent of affected individuals are under the age of 15. Medulloblastomas are extremely rare in adults accounting for 1-2 percent of all cases of brain tumors in adults. In adults, most medulloblastomas occur in individuals between 20-44 years of age. Medulloblastomas are extremely rare in individuals over the age of 45. In children, males are affected more often than females. However, in adults the ratio is the same. The exact incidence of medulloblastomas is not known and many different estimates are given the medical literature. Generally, medulloblastomas account for 2 percent of all primary brain tumors and 18 percent of all pediatric brain tumors. Approximately 1,000 new cases are diagnosed in children and adults each year in the United States.
|
Affects of Medulloblastoma. Medulloblastomas can affect individuals of any age, but occur most often in children under the age of 15 with a peak incidence between 3 and 9 years of age. Medulloblastomas are the most common malignant brain tumor in children. Approximately 80 percent of affected individuals are under the age of 15. Medulloblastomas are extremely rare in adults accounting for 1-2 percent of all cases of brain tumors in adults. In adults, most medulloblastomas occur in individuals between 20-44 years of age. Medulloblastomas are extremely rare in individuals over the age of 45. In children, males are affected more often than females. However, in adults the ratio is the same. The exact incidence of medulloblastomas is not known and many different estimates are given the medical literature. Generally, medulloblastomas account for 2 percent of all primary brain tumors and 18 percent of all pediatric brain tumors. Approximately 1,000 new cases are diagnosed in children and adults each year in the United States.
| 777 |
Medulloblastoma
|
nord_777_4
|
Related disorders of Medulloblastoma
|
Symptoms of the following disorders can be similar to those of medulloblastomas. Comparisons may be useful for a differential diagnosis. Different types of brain tumors may result in increased intracranial pressure and generalized symptoms similar to those potentially associated with medulloblastomas, such as vomiting, headaches, gait disturbances, changes in consciousness, visual impairment, enlargement of the head in young children, and/or other abnormalities. Such tumors may also result in additional generalized or more localized symptoms not typically associated with medulloblastomas; differ in average symptom duration before diagnosis; and/or have other clinical characteristics not generally seen with medulloblastomas. Clinical and neurological examination, complete patient history, advanced imaging techniques, and other diagnostic measures are typically required to confirm the presence of a brain tumor and to determine specific tumor type. (For further information, please see “Standard Therapies: Diagnosis” below or choose the specific tumor name in question as your search term in the Rare Disease Database.)
|
Related disorders of Medulloblastoma. Symptoms of the following disorders can be similar to those of medulloblastomas. Comparisons may be useful for a differential diagnosis. Different types of brain tumors may result in increased intracranial pressure and generalized symptoms similar to those potentially associated with medulloblastomas, such as vomiting, headaches, gait disturbances, changes in consciousness, visual impairment, enlargement of the head in young children, and/or other abnormalities. Such tumors may also result in additional generalized or more localized symptoms not typically associated with medulloblastomas; differ in average symptom duration before diagnosis; and/or have other clinical characteristics not generally seen with medulloblastomas. Clinical and neurological examination, complete patient history, advanced imaging techniques, and other diagnostic measures are typically required to confirm the presence of a brain tumor and to determine specific tumor type. (For further information, please see “Standard Therapies: Diagnosis” below or choose the specific tumor name in question as your search term in the Rare Disease Database.)
| 777 |
Medulloblastoma
|
nord_777_5
|
Diagnosis of Medulloblastoma
|
Medulloblastoma is diagnosed based upon thorough clinical and neurological evaluation, detection of characteristic symptoms and physical findings, patient history, and specialized diagnostic tests. Such studies may include blood tests; evaluation of visual acuity, visual fields, and eye movements; the use of an instrument (ophthalmoscope) that visualizes the inside of the eyes (i.e., to detect papilledema); advanced imaging techniques; and/or other diagnostic tests.The main specialized imaging technique used to diagnosis medulloblastoma is magnetic resonance imaging (MRI) of the brain and spine. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of organs and tissues. Experts indicate that, if available, MRI is preferable to computed tomography (CT) scanning as a diagnostic means for medulloblastomas since it may provide a better indication of tumor extent, possible invasion of the meninges, and spine involvement. An MRI is performed before and after a patient receives an intravenous injection of gadolinium-based contrast material. The contrast causes a tumor to appear as a bright mass (much brighter than surrounding tissue). When an MRI is unavailable, a CT scan may be performed. During a CT scan, a computer and x-rays are used to create a film showing cross-sectional images of internal structures.Gadolinium-based MRI of the spine may also be performed to detect whether a medulloblastoma has spread to the cerebrospinal fluid and the spine. In some cases, a lumbar puncture may also be recommended for analysis of tumor cells within the CSF. (During a lumbar puncture, a hollow needle is inserted into the spinal canal to withdraw CSF for analysis.) However, experts may advise that lumbar puncture is inadvisable (contraindicated) in most cases before tumor resection.Surgical removal and microscopic examination (biopsy) of the affected tissue may be performed to confirm a diagnosis of medulloblastoma. Other diagnostic studies may also be conducted in some instances.
|
Diagnosis of Medulloblastoma. Medulloblastoma is diagnosed based upon thorough clinical and neurological evaluation, detection of characteristic symptoms and physical findings, patient history, and specialized diagnostic tests. Such studies may include blood tests; evaluation of visual acuity, visual fields, and eye movements; the use of an instrument (ophthalmoscope) that visualizes the inside of the eyes (i.e., to detect papilledema); advanced imaging techniques; and/or other diagnostic tests.The main specialized imaging technique used to diagnosis medulloblastoma is magnetic resonance imaging (MRI) of the brain and spine. MRI uses a magnetic field and radio waves to create detailed cross-sectional images of organs and tissues. Experts indicate that, if available, MRI is preferable to computed tomography (CT) scanning as a diagnostic means for medulloblastomas since it may provide a better indication of tumor extent, possible invasion of the meninges, and spine involvement. An MRI is performed before and after a patient receives an intravenous injection of gadolinium-based contrast material. The contrast causes a tumor to appear as a bright mass (much brighter than surrounding tissue). When an MRI is unavailable, a CT scan may be performed. During a CT scan, a computer and x-rays are used to create a film showing cross-sectional images of internal structures.Gadolinium-based MRI of the spine may also be performed to detect whether a medulloblastoma has spread to the cerebrospinal fluid and the spine. In some cases, a lumbar puncture may also be recommended for analysis of tumor cells within the CSF. (During a lumbar puncture, a hollow needle is inserted into the spinal canal to withdraw CSF for analysis.) However, experts may advise that lumbar puncture is inadvisable (contraindicated) in most cases before tumor resection.Surgical removal and microscopic examination (biopsy) of the affected tissue may be performed to confirm a diagnosis of medulloblastoma. Other diagnostic studies may also be conducted in some instances.
| 777 |
Medulloblastoma
|
nord_777_6
|
Therapies of Medulloblastoma
|
TreatmentThe treatment of medulloblastoma may require the coordinated efforts of a team of medical professionals, including pediatricians; specialists in diseases of the nervous system (neurologists), the diagnosis and treatment of cancer (medical oncologists), and the use of radiation in the treatment of cancer (radiation oncologists); pediatric oncologists; oncology nurses; neurosurgeons; and/or other health care professionals. The specific treatment approaches used may depend upon tumor size, location, nature, stage, and/or progression; patient age and overall health; and other factors.Aggressive surgery followed by radiotherapy and chemotherapy, which may be used alone or in combination, are the current standard used to treat individuals with medulloblastoma. Therapies that are effective in one group may not be effective in another group. For example, chemotherapy that has been effective in children and adolescents may be ineffective or less well tolerated in adults.Surgery may be performed to obtain a biopsy sample, relieve pressure on the brain by draining CSF accumulation, and to remove as much as the tumor as possible without damaging surrounding brain tissue. Surgery is directed toward complete tumor removal or removal of as much of the tumor as possible. Some studies have indicated that the outcome improves when all of the tumor visible to a surgeon's eyes can be removed (gross total resection). However, gross total resection is not always possible. Shortly after surgery, advanced imaging techniques (e.g., CT, MRI) and other diagnostic methods may be conducted to determine how much of the tumor is left and to aid in the determination of appropriate, postoperative treatment approaches.In rare cases, shunting may be recommended before surgery to remove the tumor. Shunting will help remove excess fluid and decrease intracranial pressure. Shunts are specialized devices that drain excess CSF away from the brain to another part of the body for absorption into the bloodstream. However, preoperative CSF shunting is not routinely conducted due to certain risks (e.g., herniation, possible facilitation of the spread of cancerous cells) and since hydrocephalus is alleviated by tumor removal in many individuals. Some patients may need a shunt after the operation for tumor removal.Standard postoperative treatment often includes radiation therapy (radiotherapy) of the brain and spine (craniospinal irradiation) beginning approximately two to four weeks after surgery. During radiotherapy, radiation (via x-rays or other sources of radioactivity) is passed through selected regions of the body to destroy cancer cells and shrink tumors. Radiotherapy is provided in carefully determined dosages to help minimize damage to normal body cells. Radiotherapy is an important adjunct therapy because it can destroy microscopic cancer cells that are too small to be seen and may remain after surgery. These microscopic cells may lead to a recurrence of the tumor.In advanced cases, recommended therapy may also include treatment with certain anticancer drugs (chemotherapy) during or after radiotherapy. Physicians may recommend combination therapy with multiple chemotherapeutic drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying. Chemotherapeutic drugs that have been used to treat medulloblastoma include vincristine, lomustine, cisplatin, cyclophosphamide, carboplatin, or etoposide.Chemotherapy may be given to infants and young children under the age of three instead of radiotherapy to avoid the potential long-term side effects of radiotherapy. In some cases, radiotherapy may be recommended when those children grow older.Because there are fewer adults with medulloblastoma than children, effective treatment regimens have yet to be established for adults. The various chemotherapeutic drugs that have been used to treat children have been less effective in adults who often experience worse side effects.
|
Therapies of Medulloblastoma. TreatmentThe treatment of medulloblastoma may require the coordinated efforts of a team of medical professionals, including pediatricians; specialists in diseases of the nervous system (neurologists), the diagnosis and treatment of cancer (medical oncologists), and the use of radiation in the treatment of cancer (radiation oncologists); pediatric oncologists; oncology nurses; neurosurgeons; and/or other health care professionals. The specific treatment approaches used may depend upon tumor size, location, nature, stage, and/or progression; patient age and overall health; and other factors.Aggressive surgery followed by radiotherapy and chemotherapy, which may be used alone or in combination, are the current standard used to treat individuals with medulloblastoma. Therapies that are effective in one group may not be effective in another group. For example, chemotherapy that has been effective in children and adolescents may be ineffective or less well tolerated in adults.Surgery may be performed to obtain a biopsy sample, relieve pressure on the brain by draining CSF accumulation, and to remove as much as the tumor as possible without damaging surrounding brain tissue. Surgery is directed toward complete tumor removal or removal of as much of the tumor as possible. Some studies have indicated that the outcome improves when all of the tumor visible to a surgeon's eyes can be removed (gross total resection). However, gross total resection is not always possible. Shortly after surgery, advanced imaging techniques (e.g., CT, MRI) and other diagnostic methods may be conducted to determine how much of the tumor is left and to aid in the determination of appropriate, postoperative treatment approaches.In rare cases, shunting may be recommended before surgery to remove the tumor. Shunting will help remove excess fluid and decrease intracranial pressure. Shunts are specialized devices that drain excess CSF away from the brain to another part of the body for absorption into the bloodstream. However, preoperative CSF shunting is not routinely conducted due to certain risks (e.g., herniation, possible facilitation of the spread of cancerous cells) and since hydrocephalus is alleviated by tumor removal in many individuals. Some patients may need a shunt after the operation for tumor removal.Standard postoperative treatment often includes radiation therapy (radiotherapy) of the brain and spine (craniospinal irradiation) beginning approximately two to four weeks after surgery. During radiotherapy, radiation (via x-rays or other sources of radioactivity) is passed through selected regions of the body to destroy cancer cells and shrink tumors. Radiotherapy is provided in carefully determined dosages to help minimize damage to normal body cells. Radiotherapy is an important adjunct therapy because it can destroy microscopic cancer cells that are too small to be seen and may remain after surgery. These microscopic cells may lead to a recurrence of the tumor.In advanced cases, recommended therapy may also include treatment with certain anticancer drugs (chemotherapy) during or after radiotherapy. Physicians may recommend combination therapy with multiple chemotherapeutic drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying. Chemotherapeutic drugs that have been used to treat medulloblastoma include vincristine, lomustine, cisplatin, cyclophosphamide, carboplatin, or etoposide.Chemotherapy may be given to infants and young children under the age of three instead of radiotherapy to avoid the potential long-term side effects of radiotherapy. In some cases, radiotherapy may be recommended when those children grow older.Because there are fewer adults with medulloblastoma than children, effective treatment regimens have yet to be established for adults. The various chemotherapeutic drugs that have been used to treat children have been less effective in adults who often experience worse side effects.
| 777 |
Medulloblastoma
|
nord_778_0
|
Overview of MEF2C Deficiency
|
SummaryMEF2C deficiency is an extremely rare genetic disorder caused by a change (mutation) in the MEF2C gene. This mutation, often a deletion, leads to the dysfunction of MEF2C protein which is essential to the proper functioning of the musculoskeletal, cardiovascular, neurological, craniofacial, and immune systems. A deletion mutation occurs when a portion of a chromosome is missing. Signs and symptoms vary greatly and usually first present when the patient is between one and two years old. Some of the most common presenting symptoms are decreased muscle tone (hypotonia), global developmental delay, seizures and brain abnormalities. Currently, there is no treatment for MEF2C deficiency and care is individualized based on symptoms. Anti-seizure medications are prescribed for seizures, melatonin may be used for sleep difficulties, and physical, occupational, and speech therapy are prescribed for developmental delays.IntroductionThe MEF2C gene was discovered in 2008 by Dr. Stuart Lipton and his research team at the Burnham Institute. Originally, Dr. Lipton’s study demonstrated that disruption of the function of the MEF2C gene resulted in mice having smaller brains, a decreased number of neurons, and severe autism-like abnormalities. Mutations in the MEF2C gene are included in the list of mutations associated with a Rett-like phenotype, such as Rett syndrome, Angelman syndrome, Pitt-Hopkins syndrome, CDKL5 deficiency disorder and many autism-linked genes.
|
Overview of MEF2C Deficiency. SummaryMEF2C deficiency is an extremely rare genetic disorder caused by a change (mutation) in the MEF2C gene. This mutation, often a deletion, leads to the dysfunction of MEF2C protein which is essential to the proper functioning of the musculoskeletal, cardiovascular, neurological, craniofacial, and immune systems. A deletion mutation occurs when a portion of a chromosome is missing. Signs and symptoms vary greatly and usually first present when the patient is between one and two years old. Some of the most common presenting symptoms are decreased muscle tone (hypotonia), global developmental delay, seizures and brain abnormalities. Currently, there is no treatment for MEF2C deficiency and care is individualized based on symptoms. Anti-seizure medications are prescribed for seizures, melatonin may be used for sleep difficulties, and physical, occupational, and speech therapy are prescribed for developmental delays.IntroductionThe MEF2C gene was discovered in 2008 by Dr. Stuart Lipton and his research team at the Burnham Institute. Originally, Dr. Lipton’s study demonstrated that disruption of the function of the MEF2C gene resulted in mice having smaller brains, a decreased number of neurons, and severe autism-like abnormalities. Mutations in the MEF2C gene are included in the list of mutations associated with a Rett-like phenotype, such as Rett syndrome, Angelman syndrome, Pitt-Hopkins syndrome, CDKL5 deficiency disorder and many autism-linked genes.
| 778 |
MEF2C Deficiency
|
nord_778_1
|
Symptoms of MEF2C Deficiency
|
Typically, there are no distinctive signs during pregnancy or delivery of a child with MEF2C deficiency. The individual seems to develop normally in the neonatal period and it is not until infancy or early childhood when symptoms such as hypotonia, feeding difficulties and poor eye contact appear. Seizures may occur, especially when the baby has an illness or fever. Global developmental delay is found in nearly all MEF2C deficiency patients. There is variety in these developmental delays, specifically with speech, gait, cognitive abilities and social skills. These patients also present with some mild to severe distinctive facial features.Children with MEF2C deficiency usually have a variety of brain abnormalities. Brain MRIs of patients with MEF2C deficiency may show a loss of brain cells, enlargement of ventricles, or abnormal corpus callosum. MEF2C protein has been found to play a role in decreased forebrain development both dorsally and ventrally.MEF2C patients will likely have epilepsy, but the age of onset and type of seizures varies. Most commonly, the patient develops seizures in infancy. Some of the seizures that patients experience are infantile spasms, febrile, partial, absence, tonic clonic, and myoclonic seizures. It has been found that phenotypic (symptom) severity may be associated with the site of mutation within the MEF2C gene.Summary of symptoms:NEUROLOGICALBEHAVIORALDEVELOPMENTAL DELAYMUSCULOSKELETALVISIONRESPIRATORYGASTROINTESTINALCRANIOFACIALCARDIOVASCULARDERMATOLOGICALOTHER LESS COMMON SYMPTOMS
|
Symptoms of MEF2C Deficiency. Typically, there are no distinctive signs during pregnancy or delivery of a child with MEF2C deficiency. The individual seems to develop normally in the neonatal period and it is not until infancy or early childhood when symptoms such as hypotonia, feeding difficulties and poor eye contact appear. Seizures may occur, especially when the baby has an illness or fever. Global developmental delay is found in nearly all MEF2C deficiency patients. There is variety in these developmental delays, specifically with speech, gait, cognitive abilities and social skills. These patients also present with some mild to severe distinctive facial features.Children with MEF2C deficiency usually have a variety of brain abnormalities. Brain MRIs of patients with MEF2C deficiency may show a loss of brain cells, enlargement of ventricles, or abnormal corpus callosum. MEF2C protein has been found to play a role in decreased forebrain development both dorsally and ventrally.MEF2C patients will likely have epilepsy, but the age of onset and type of seizures varies. Most commonly, the patient develops seizures in infancy. Some of the seizures that patients experience are infantile spasms, febrile, partial, absence, tonic clonic, and myoclonic seizures. It has been found that phenotypic (symptom) severity may be associated with the site of mutation within the MEF2C gene.Summary of symptoms:NEUROLOGICALBEHAVIORALDEVELOPMENTAL DELAYMUSCULOSKELETALVISIONRESPIRATORYGASTROINTESTINALCRANIOFACIALCARDIOVASCULARDERMATOLOGICALOTHER LESS COMMON SYMPTOMS
| 778 |
MEF2C Deficiency
|
nord_778_2
|
Causes of MEF2C Deficiency
|
MEF2C deficiency is caused by mutations in the MEF2C gene or in the gene’s promoter and enhancer regions, resulting in a lack or total absence of functional MEF2C protein. In most cases, MEF2C deficiency is de novo, meaning it is caused by spontaneous changes in DNA sequence and not inherited from a patient’s parents. The MEF2C gene codes for a transcription factor that is involved in normal development of the heart, brain, craniofacial, vascular (blood flow), and immune systems of the body. The MEF2C enhancer region is widely expressed in glial cells, which are cells that support brain and nervous system cells. The MEF2C gene can have these mutations within the gene or upstream in the enhancer or promoter regions. The enhancer and promoter regions of the gene are called regulatory elements. These are DNA elements that help “turn on” the gene in order to transcribe and translate more MEF2C protein. MEF2C deficiency may also be called MEF2C haploinsufficiency, which is a characteristic of an autosomal dominant disorder. This means that one functional copy of the gene is not sufficient to ensure that child will not have the disease. MEF2C protein is a transcription factor, which means it helps activate the transcription of other genes. When MEF2C protein is absent or dysfunctional, the genes for which it promotes transcription are also affected. These genes include MECP2 and CDKL5, which also play a role in Rett syndrome and CDKL5 deficiency disorder. Therefore, loss of MEF2C function leads to diminished activation of these other genes, resulting in Rett-like or CDKL5 deficiency-like symptoms. The severity of symptoms of MEF2C deficiency are dependent upon the amount of gene affected by the mutation, with larger abnormalities reflective of more severe symptoms of the syndrome.
|
Causes of MEF2C Deficiency. MEF2C deficiency is caused by mutations in the MEF2C gene or in the gene’s promoter and enhancer regions, resulting in a lack or total absence of functional MEF2C protein. In most cases, MEF2C deficiency is de novo, meaning it is caused by spontaneous changes in DNA sequence and not inherited from a patient’s parents. The MEF2C gene codes for a transcription factor that is involved in normal development of the heart, brain, craniofacial, vascular (blood flow), and immune systems of the body. The MEF2C enhancer region is widely expressed in glial cells, which are cells that support brain and nervous system cells. The MEF2C gene can have these mutations within the gene or upstream in the enhancer or promoter regions. The enhancer and promoter regions of the gene are called regulatory elements. These are DNA elements that help “turn on” the gene in order to transcribe and translate more MEF2C protein. MEF2C deficiency may also be called MEF2C haploinsufficiency, which is a characteristic of an autosomal dominant disorder. This means that one functional copy of the gene is not sufficient to ensure that child will not have the disease. MEF2C protein is a transcription factor, which means it helps activate the transcription of other genes. When MEF2C protein is absent or dysfunctional, the genes for which it promotes transcription are also affected. These genes include MECP2 and CDKL5, which also play a role in Rett syndrome and CDKL5 deficiency disorder. Therefore, loss of MEF2C function leads to diminished activation of these other genes, resulting in Rett-like or CDKL5 deficiency-like symptoms. The severity of symptoms of MEF2C deficiency are dependent upon the amount of gene affected by the mutation, with larger abnormalities reflective of more severe symptoms of the syndrome.
| 778 |
MEF2C Deficiency
|
nord_778_3
|
Affects of MEF2C Deficiency
|
MEF2C deficiency appears to equally affect males and females, and it does not seem to have an ethnic predisposition. The age of onset is most commonly in infancy or early childhood. MEF2C deficiency is often misdiagnosed as Rett syndrome due to its Rett-like phenotype. There have been around 50 patients identified with MEF2C deficiency, but this number should likely be larger due to misdiagnosis of subtle symptoms that present similarly to other more well-known disorders.
|
Affects of MEF2C Deficiency. MEF2C deficiency appears to equally affect males and females, and it does not seem to have an ethnic predisposition. The age of onset is most commonly in infancy or early childhood. MEF2C deficiency is often misdiagnosed as Rett syndrome due to its Rett-like phenotype. There have been around 50 patients identified with MEF2C deficiency, but this number should likely be larger due to misdiagnosis of subtle symptoms that present similarly to other more well-known disorders.
| 778 |
MEF2C Deficiency
|
nord_778_4
|
Related disorders of MEF2C Deficiency
|
MEF2C deficiency has clinical overlap with Rett Syndrome, Angelman Syndrome, Pitt-Hopkins syndrome, and CDKL5 deficiency disorder. Often, these syndromes are grouped under the term “Rett-like”, but using this term has recently been discouraged because these syndromes are now recognized as clinically different from each other. Symptoms of the following disorders can be similar to those of MEF2C deficiency. Comparisons may be useful for a differential diagnosis. Rett syndrome is a rare neurodevelopmental disorder that mostly affects females. Infants with Rett syndrome develop normally for about 7 to 18 months after birth. Then, they begin to lose certain developmental milestones such as language production and purposeful hand movements. They also have other symptoms such as uncontrolled hand movements, ataxia, microcephaly, and many features of autism spectrum disorder. Rett syndrome is caused by mutations in the MECP2 gene and result in a wide range of disability. The symptoms of MEF2C deficiency present similar to Rett syndrome symptoms, such as motor delay and stereotypical behavior, but unlike Rett syndrome, there is typically no microcephaly or regression of development. Also, seizures begin later in development and are less severe in MEF2C deficiency compared to Rett syndrome. (For more information on this disorder, choose “Rett” as your search term in the Rare Disease Database.) Angelman syndrome is a rare neurological disorder that presents with developmental delay, learning disabilities, speech difficulties, ataxia, jerky movements of limbs, happy mood, and unexpected laughter episodes. More common symptoms include seizures and sleep difficulties. Angelman syndrome is caused by a mutation in the UBE3A gene. The symptoms of MEF2C deficiency are similar to the symptoms of Angelman syndrome, but unlike Angelman syndrome, there is typically no microcephaly. Neither syndrome involves neurodevelopmental regression. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database). Pitt-Hopkins syndrome (PTHS) is a rare neurological disorder. Common symptoms of this disorder are speech difficulties, seizures, abnormal breathing patterns, ataxia, distinctive facial features, intellectual disability, and other delays in reaching developmental milestones. People with PTHS are often very social and happy. Pitt-Hopkins syndrome is caused by a mutation in the TCF4 gene. Pitt-Hopkins syndrome presents with similar motor and cognitive delays to patients with MEF2C deficiency. However, they can be differentiated because patients with Pitt-Hopkins typically experience more severe respiratory symptoms such as hyperventilation or breath-holding spells that may result in a loss of consciousness. (For more information on this disorder, choose “Pitt-Hopkins” as your search term in the Rare Disease Database). CDKL5 deficiency disorder is a rare X-linked disorder causing neurodevelopmental impairment. People with this disorder will likely have seizures during their first few months of life. They have severe motor and language developmental disabilities. Additionally, these patients will experience cognitive disabilities and stereotypic hand movements. CDKL5 deficiency disorder is caused by a mutation in the CDKL5 gene. Many of the symptoms experienced by these patients are similar to those of MEF2C deficiency. (For more information on this disorder, choose “CDKL5 deficiency” as your search term in the Rare Disease Database).
|
Related disorders of MEF2C Deficiency. MEF2C deficiency has clinical overlap with Rett Syndrome, Angelman Syndrome, Pitt-Hopkins syndrome, and CDKL5 deficiency disorder. Often, these syndromes are grouped under the term “Rett-like”, but using this term has recently been discouraged because these syndromes are now recognized as clinically different from each other. Symptoms of the following disorders can be similar to those of MEF2C deficiency. Comparisons may be useful for a differential diagnosis. Rett syndrome is a rare neurodevelopmental disorder that mostly affects females. Infants with Rett syndrome develop normally for about 7 to 18 months after birth. Then, they begin to lose certain developmental milestones such as language production and purposeful hand movements. They also have other symptoms such as uncontrolled hand movements, ataxia, microcephaly, and many features of autism spectrum disorder. Rett syndrome is caused by mutations in the MECP2 gene and result in a wide range of disability. The symptoms of MEF2C deficiency present similar to Rett syndrome symptoms, such as motor delay and stereotypical behavior, but unlike Rett syndrome, there is typically no microcephaly or regression of development. Also, seizures begin later in development and are less severe in MEF2C deficiency compared to Rett syndrome. (For more information on this disorder, choose “Rett” as your search term in the Rare Disease Database.) Angelman syndrome is a rare neurological disorder that presents with developmental delay, learning disabilities, speech difficulties, ataxia, jerky movements of limbs, happy mood, and unexpected laughter episodes. More common symptoms include seizures and sleep difficulties. Angelman syndrome is caused by a mutation in the UBE3A gene. The symptoms of MEF2C deficiency are similar to the symptoms of Angelman syndrome, but unlike Angelman syndrome, there is typically no microcephaly. Neither syndrome involves neurodevelopmental regression. (For more information on this disorder, choose “Angelman” as your search term in the Rare Disease Database). Pitt-Hopkins syndrome (PTHS) is a rare neurological disorder. Common symptoms of this disorder are speech difficulties, seizures, abnormal breathing patterns, ataxia, distinctive facial features, intellectual disability, and other delays in reaching developmental milestones. People with PTHS are often very social and happy. Pitt-Hopkins syndrome is caused by a mutation in the TCF4 gene. Pitt-Hopkins syndrome presents with similar motor and cognitive delays to patients with MEF2C deficiency. However, they can be differentiated because patients with Pitt-Hopkins typically experience more severe respiratory symptoms such as hyperventilation or breath-holding spells that may result in a loss of consciousness. (For more information on this disorder, choose “Pitt-Hopkins” as your search term in the Rare Disease Database). CDKL5 deficiency disorder is a rare X-linked disorder causing neurodevelopmental impairment. People with this disorder will likely have seizures during their first few months of life. They have severe motor and language developmental disabilities. Additionally, these patients will experience cognitive disabilities and stereotypic hand movements. CDKL5 deficiency disorder is caused by a mutation in the CDKL5 gene. Many of the symptoms experienced by these patients are similar to those of MEF2C deficiency. (For more information on this disorder, choose “CDKL5 deficiency” as your search term in the Rare Disease Database).
| 778 |
MEF2C Deficiency
|
nord_778_5
|
Diagnosis of MEF2C Deficiency
|
Hypotonia and epilepsy are symptoms that may lead to a suspicion of MEF2C deficiency. MEF2C deficiency can be diagnosed with a chromosomal microarray or fluorescence in situ hybridization (FISH) test to look for very small missing pieces in the region on chromosome 5 where the MEF2C gene is located. For even smaller chromosomal abnormalities, a multiplex ligation-dependent probe amplification (MPLA) test may also be used.Molecular genetic testing using whole exome or whole genome sequencing is also available to look for pathogenic variants (mutations) in the MEF2C gene.
|
Diagnosis of MEF2C Deficiency. Hypotonia and epilepsy are symptoms that may lead to a suspicion of MEF2C deficiency. MEF2C deficiency can be diagnosed with a chromosomal microarray or fluorescence in situ hybridization (FISH) test to look for very small missing pieces in the region on chromosome 5 where the MEF2C gene is located. For even smaller chromosomal abnormalities, a multiplex ligation-dependent probe amplification (MPLA) test may also be used.Molecular genetic testing using whole exome or whole genome sequencing is also available to look for pathogenic variants (mutations) in the MEF2C gene.
| 778 |
MEF2C Deficiency
|
nord_778_6
|
Therapies of MEF2C Deficiency
|
Treatment
There are currently no approved therapies that specifically target MEF2C deficiency. A multidisciplinary approach to treatment is required involving the following specialists, therapies and tests:Many of the other treatments that these patients receive are similar to what children with autism spectrum disorder or other neurodevelopmental disorders would receive. Typically, seizures are well-controlled by various medications. Melatonin may be used for sleep difficulties.Genetic counseling is recommended for families with affected children.
|
Therapies of MEF2C Deficiency. Treatment
There are currently no approved therapies that specifically target MEF2C deficiency. A multidisciplinary approach to treatment is required involving the following specialists, therapies and tests:Many of the other treatments that these patients receive are similar to what children with autism spectrum disorder or other neurodevelopmental disorders would receive. Typically, seizures are well-controlled by various medications. Melatonin may be used for sleep difficulties.Genetic counseling is recommended for families with affected children.
| 778 |
MEF2C Deficiency
|
nord_779_0
|
Overview of Megalencephaly-Capillary Malformation
|
SummaryMegalencephaly-capillary malformation syndrome (MCAP), formerly known as macrocephaly-capillary malformation, is a complex disorder that involves many organ systems including the skin, blood vessels, connective tissue, brain and others, and that usually manifests at birth. i. Most affected individuals have a disproportionately large head and vascular malformations including capillary malformations on the skin of the midline face, trunk and limbs. These capillary malformations often show a lacy or reticulated pattern (resembling a net or web, and are sometimes termed “cutis marmorata”). Most children with MCAP have an enlarged brain (or megalencephaly) and other findings on brain MRI scans with associated neurological problems.IntroductionMultiple terms have been used in the past for this syndrome. The earliest one was macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) because the vascular lesions were believed to be consistent with CMTC. However, careful examination of the skin in these children revealed that the vascular lesions are not CMTC but rather capillary malformations (described below), and so the syndrome was accurately renamed to “macrocephaly-capillary malformation syndrome” (or M-CM). Recently, the name was modified from this latter term to “megalencephaly-capillary malformation” (or MCAP, in short) because the term “macrocephaly” refers to a large head due various causes, whereas “megalencephaly” is a more specific and accurate term that refers to the truly enlarged brain present in this syndrome.
|
Overview of Megalencephaly-Capillary Malformation. SummaryMegalencephaly-capillary malformation syndrome (MCAP), formerly known as macrocephaly-capillary malformation, is a complex disorder that involves many organ systems including the skin, blood vessels, connective tissue, brain and others, and that usually manifests at birth. i. Most affected individuals have a disproportionately large head and vascular malformations including capillary malformations on the skin of the midline face, trunk and limbs. These capillary malformations often show a lacy or reticulated pattern (resembling a net or web, and are sometimes termed “cutis marmorata”). Most children with MCAP have an enlarged brain (or megalencephaly) and other findings on brain MRI scans with associated neurological problems.IntroductionMultiple terms have been used in the past for this syndrome. The earliest one was macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) because the vascular lesions were believed to be consistent with CMTC. However, careful examination of the skin in these children revealed that the vascular lesions are not CMTC but rather capillary malformations (described below), and so the syndrome was accurately renamed to “macrocephaly-capillary malformation syndrome” (or M-CM). Recently, the name was modified from this latter term to “megalencephaly-capillary malformation” (or MCAP, in short) because the term “macrocephaly” refers to a large head due various causes, whereas “megalencephaly” is a more specific and accurate term that refers to the truly enlarged brain present in this syndrome.
| 779 |
Megalencephaly-Capillary Malformation
|
nord_779_1
|
Symptoms of Megalencephaly-Capillary Malformation
|
The symptoms and severity of MCAP vary greatly from one person to another. Some individuals may develop milder symptoms, while others have more serious complications and it is important to note that affected individuals may not have all of the symptoms discussed below. Families of affected children should talk to their physician and medical team about their specific features, associated symptoms and discuss their medical management and overall prognosis.Growth abnormalitiesThe vast majority of infants born with MCAP have an abnormally large head (or megalencephaly) at birth that tends to be progressive, and maybe associated with a large body size at birth (i.e., somatic overgrowth or macrosomia). In most infants with body overgrowth birth, the overgrowth tends to either stay stable, decrease or normalize with age, and some may experience growth deficiency after birth. Infants and children may also display an asymmetric growth pattern, which ranges from one side of the body being clearly larger than the other (frank hemihypertrophy), to more subtle asymmetries of the body.Vascular abnormalitiesAs newborns, children with MCAP have distinctive skin lesions that may be scattered over the trunk, limbs, and midline face. These skin findings are most often a specific type of vascular malformation known as capillary malformations. Capillaries are tiny blood vessels that form a fine network throughout the body connecting arteries and veins and are responsible for the exchange of various substances such as oxygen between cells and tissues. When abnormally widened (dilated) or malformed, these distinctive skin lesions appear. The most common location is the midline face (on the forehead, or above the upper lip), in which case the term nevus flammeus (or more commonly “Salmon patch”) is used. These facial lesions occur in a significant number of healthy children. Therefore their presence alone does not establish the diagnosis of MCAP. And while they may fade as children with MCAP grow older, they can persist to variable degrees. Other commonly seen lesions include cutis marmorata, which are generalized capillary malformations that may range from subtle lesions resembling the common marbled appearance of the skin of Caucasian infants to more recognizable lesions that persist. Finally, some children have infantile hemangiomas that may occur anywhere on the body. These may also persist in some children and, rarely, occur in internal organs (e.g., liver, spleen as well).Brain abnormalitiesBesides megalencephaly, children with MCAP may develop abnormal widening of the sac-like spaces (ventricles) of the brain that contain cerebrospinal fluid (or ventriculomegaly). Excessive accumulation of fluid may lead to hydrocephalus, one of the potentially serious complications of this syndrome. Furthermore, enlargement and herniation of the cerebellar tonsils (or a Chiari malformation) may occur which may also lead to hydrocephalus and brainstem compression. Given these two potentially serious complications of this syndrome, it is recommended that children are regularly monitored for symptoms related to hydrocephalus and cerebellar tonsillar herniation, such as headaches, lethargy, breathing abnormalities, and recurrent vomiting.Additional structural abnormalities of the brain have been reported in MCAP including cerebellar/cerebral asymmetry, abnormalities in the development of the cerebral cortex (cortical dysplasia), and white matter abnormalities. One particularly common type of cortical malformation in MCAP is polymicrogyria (PMG), which refers to abnormally small and numerous folds of the cortical surface. The corpus callosum (a midline structure that joins the two cerebral hemispheres) is usually twice as thick as normal.Given all of these brain abnormalities, children with MCAP are at greater risk than the general population of developing associated neurological abnormalities including developmental delay and neurocognitive impairment (ranging from mild to severe), seizures and tone abnormalities.Digital abnormalities and other physical features of MCAP syndromeInfants with MCAP commonly have webbing of the digits (or syndactyly) that may involve the 2nd-3rd and 4th fingers or toes. Other physical abnormalities include a prominent forehead (frontal bossing), extra fingers and toes (polydactyly), loose (hyperelastic) skin, and loose joints (joint laxity). Secondary to abnormal growth, affected infants may also experience unequal development of the face and legs (facial and limb asymmetry). In rare cases, congenital heart defects, abnormal heart rhythms (arrhythmias), and genitourinary abnormalities may occur.
|
Symptoms of Megalencephaly-Capillary Malformation. The symptoms and severity of MCAP vary greatly from one person to another. Some individuals may develop milder symptoms, while others have more serious complications and it is important to note that affected individuals may not have all of the symptoms discussed below. Families of affected children should talk to their physician and medical team about their specific features, associated symptoms and discuss their medical management and overall prognosis.Growth abnormalitiesThe vast majority of infants born with MCAP have an abnormally large head (or megalencephaly) at birth that tends to be progressive, and maybe associated with a large body size at birth (i.e., somatic overgrowth or macrosomia). In most infants with body overgrowth birth, the overgrowth tends to either stay stable, decrease or normalize with age, and some may experience growth deficiency after birth. Infants and children may also display an asymmetric growth pattern, which ranges from one side of the body being clearly larger than the other (frank hemihypertrophy), to more subtle asymmetries of the body.Vascular abnormalitiesAs newborns, children with MCAP have distinctive skin lesions that may be scattered over the trunk, limbs, and midline face. These skin findings are most often a specific type of vascular malformation known as capillary malformations. Capillaries are tiny blood vessels that form a fine network throughout the body connecting arteries and veins and are responsible for the exchange of various substances such as oxygen between cells and tissues. When abnormally widened (dilated) or malformed, these distinctive skin lesions appear. The most common location is the midline face (on the forehead, or above the upper lip), in which case the term nevus flammeus (or more commonly “Salmon patch”) is used. These facial lesions occur in a significant number of healthy children. Therefore their presence alone does not establish the diagnosis of MCAP. And while they may fade as children with MCAP grow older, they can persist to variable degrees. Other commonly seen lesions include cutis marmorata, which are generalized capillary malformations that may range from subtle lesions resembling the common marbled appearance of the skin of Caucasian infants to more recognizable lesions that persist. Finally, some children have infantile hemangiomas that may occur anywhere on the body. These may also persist in some children and, rarely, occur in internal organs (e.g., liver, spleen as well).Brain abnormalitiesBesides megalencephaly, children with MCAP may develop abnormal widening of the sac-like spaces (ventricles) of the brain that contain cerebrospinal fluid (or ventriculomegaly). Excessive accumulation of fluid may lead to hydrocephalus, one of the potentially serious complications of this syndrome. Furthermore, enlargement and herniation of the cerebellar tonsils (or a Chiari malformation) may occur which may also lead to hydrocephalus and brainstem compression. Given these two potentially serious complications of this syndrome, it is recommended that children are regularly monitored for symptoms related to hydrocephalus and cerebellar tonsillar herniation, such as headaches, lethargy, breathing abnormalities, and recurrent vomiting.Additional structural abnormalities of the brain have been reported in MCAP including cerebellar/cerebral asymmetry, abnormalities in the development of the cerebral cortex (cortical dysplasia), and white matter abnormalities. One particularly common type of cortical malformation in MCAP is polymicrogyria (PMG), which refers to abnormally small and numerous folds of the cortical surface. The corpus callosum (a midline structure that joins the two cerebral hemispheres) is usually twice as thick as normal.Given all of these brain abnormalities, children with MCAP are at greater risk than the general population of developing associated neurological abnormalities including developmental delay and neurocognitive impairment (ranging from mild to severe), seizures and tone abnormalities.Digital abnormalities and other physical features of MCAP syndromeInfants with MCAP commonly have webbing of the digits (or syndactyly) that may involve the 2nd-3rd and 4th fingers or toes. Other physical abnormalities include a prominent forehead (frontal bossing), extra fingers and toes (polydactyly), loose (hyperelastic) skin, and loose joints (joint laxity). Secondary to abnormal growth, affected infants may also experience unequal development of the face and legs (facial and limb asymmetry). In rare cases, congenital heart defects, abnormal heart rhythms (arrhythmias), and genitourinary abnormalities may occur.
| 779 |
Megalencephaly-Capillary Malformation
|
nord_779_2
|
Causes of Megalencephaly-Capillary Malformation
|
Most cases of MCAP are caused by variants in the PIK3CA gene. Most of the identified variants are not inherited, but occur in a fraction of cells as the baby develops (I.e., post-zygotic mutations). While there are reports of family members with large heads (or megalencephaly), recurrence in family members (e.g., siblings or parents) with MCAP have been reported in the medical literature. Advanced paternal age has been noted in some patients but this association is not proven.
|
Causes of Megalencephaly-Capillary Malformation. Most cases of MCAP are caused by variants in the PIK3CA gene. Most of the identified variants are not inherited, but occur in a fraction of cells as the baby develops (I.e., post-zygotic mutations). While there are reports of family members with large heads (or megalencephaly), recurrence in family members (e.g., siblings or parents) with MCAP have been reported in the medical literature. Advanced paternal age has been noted in some patients but this association is not proven.
| 779 |
Megalencephaly-Capillary Malformation
|
nord_779_3
|
Affects of Megalencephaly-Capillary Malformation
|
The exact incidence of macrocephaly-capillary malformation is unknown. Since its first description as a distinct entity in 1997, more than 200 affected individuals have been reported. Some patients may go unrecognized or misdiagnosed making it difficult to determine the true frequency of MCAP in the general population. Males and females appear to be affected in equal numbers.
|
Affects of Megalencephaly-Capillary Malformation. The exact incidence of macrocephaly-capillary malformation is unknown. Since its first description as a distinct entity in 1997, more than 200 affected individuals have been reported. Some patients may go unrecognized or misdiagnosed making it difficult to determine the true frequency of MCAP in the general population. Males and females appear to be affected in equal numbers.
| 779 |
Megalencephaly-Capillary Malformation
|
nord_779_4
|
Related disorders of Megalencephaly-Capillary Malformation
|
Symptoms of the following disorders can be similar to those of MCAP syndrome. Comparisons may be useful for a differential diagnosis.Cutis marmorata telangiectatica congenita (CMTC) is a rare type of vascular malformation composed predominantly of capillary and vein-sized vessels within the skin. The skin lesions are characterized by a lace-like vascular pattern that are often pink-purple in color and may involve a limited or more widespread area of the skin surface. As a result, the skin has a purple or blue marbled or “fishnet” appearance resembling cutis marmorata. In some affected individuals, thinning of the skin (atrophy), breakdown (ulceration) or complete absence of the skin in affected areas may also be present. From 27 to 50 percent (see references) of affected individuals have additional associated abnormalities including pink or dark red, irregularly shaped patches of skin (capillary malformation, port wine stain, nevus flammeus); loss of muscle tissue (wasting) on one side of the body (hemiatrophy); elevated fluid pressure within the eye (glaucoma); and/or reduced growth of one leg. (For more information on this disorder, choose “cutis marmorata telangiectasia congenita” as your search term in the Rare Disease Database.)Klippel-Trenaunay syndrome, a rare disorder that is present at birth (congenital), is characterized by the presence of a capillary vascular malformation (port wine stain) on the skin of an arm or leg (cutaneous) occurring in association with) excessive growth (hypertrophy) of the soft tissue and bone of that leg and/or arm (limb), and varicose veins (venous malformations). Some affected individuals will also have an underlying lymphatic malformation of the affected limb. In individuals with the disorder, such hypertrophy typically affects one limb or one side of the body (hemihypertrophy). The symptoms and findings associated with the disorder may vary in range and severity from person to person. Some children with this syndrome have been found to have mutations of PIK3CA, the same gene associated with MCAP suggesting that KTS and MCAP are part of the same large spectrum of conditions (For more information on this disorder, choose “Klippel-Trenaunay” as your search term in the Rare Disease Database.)Megalencephaly polymicrogyria-polydactyly hydrocephalus (MPPH) syndrome is a rare disorder characterized by an abnormally large brain (megalencephaly), extra fingers or toes (polydactyly), the accumulation of excessive cerebrospinal fluid in the skull (hydrocephalus), and polymicrogyria, a condition in which the brain has too many folds or ridges that are also abnormally small. The symptoms of MPPH syndrome show great overlap with macrocephaly-capillary malformation and one report in the medical literature suggested that the two disorders may actually be different expressions of one disease spectrum. MPPH syndrome is caused by mutations in three genes: PIK3R2, AKT3 and CCND2.Additional disorders may have symptoms and physical findings that are similar to macrocephaly-capillary malformation including Sturge-Weber syndrome, Beckwith-Wiedemann syndrome, PTEN hamartoma syndrome, Proteus syndrome, Costello syndrome, Sotos syndrome and CLOVES syndrome. These disorders usually have additional findings that distinguish them from macrocephaly-capillary malformation. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
|
Related disorders of Megalencephaly-Capillary Malformation. Symptoms of the following disorders can be similar to those of MCAP syndrome. Comparisons may be useful for a differential diagnosis.Cutis marmorata telangiectatica congenita (CMTC) is a rare type of vascular malformation composed predominantly of capillary and vein-sized vessels within the skin. The skin lesions are characterized by a lace-like vascular pattern that are often pink-purple in color and may involve a limited or more widespread area of the skin surface. As a result, the skin has a purple or blue marbled or “fishnet” appearance resembling cutis marmorata. In some affected individuals, thinning of the skin (atrophy), breakdown (ulceration) or complete absence of the skin in affected areas may also be present. From 27 to 50 percent (see references) of affected individuals have additional associated abnormalities including pink or dark red, irregularly shaped patches of skin (capillary malformation, port wine stain, nevus flammeus); loss of muscle tissue (wasting) on one side of the body (hemiatrophy); elevated fluid pressure within the eye (glaucoma); and/or reduced growth of one leg. (For more information on this disorder, choose “cutis marmorata telangiectasia congenita” as your search term in the Rare Disease Database.)Klippel-Trenaunay syndrome, a rare disorder that is present at birth (congenital), is characterized by the presence of a capillary vascular malformation (port wine stain) on the skin of an arm or leg (cutaneous) occurring in association with) excessive growth (hypertrophy) of the soft tissue and bone of that leg and/or arm (limb), and varicose veins (venous malformations). Some affected individuals will also have an underlying lymphatic malformation of the affected limb. In individuals with the disorder, such hypertrophy typically affects one limb or one side of the body (hemihypertrophy). The symptoms and findings associated with the disorder may vary in range and severity from person to person. Some children with this syndrome have been found to have mutations of PIK3CA, the same gene associated with MCAP suggesting that KTS and MCAP are part of the same large spectrum of conditions (For more information on this disorder, choose “Klippel-Trenaunay” as your search term in the Rare Disease Database.)Megalencephaly polymicrogyria-polydactyly hydrocephalus (MPPH) syndrome is a rare disorder characterized by an abnormally large brain (megalencephaly), extra fingers or toes (polydactyly), the accumulation of excessive cerebrospinal fluid in the skull (hydrocephalus), and polymicrogyria, a condition in which the brain has too many folds or ridges that are also abnormally small. The symptoms of MPPH syndrome show great overlap with macrocephaly-capillary malformation and one report in the medical literature suggested that the two disorders may actually be different expressions of one disease spectrum. MPPH syndrome is caused by mutations in three genes: PIK3R2, AKT3 and CCND2.Additional disorders may have symptoms and physical findings that are similar to macrocephaly-capillary malformation including Sturge-Weber syndrome, Beckwith-Wiedemann syndrome, PTEN hamartoma syndrome, Proteus syndrome, Costello syndrome, Sotos syndrome and CLOVES syndrome. These disorders usually have additional findings that distinguish them from macrocephaly-capillary malformation. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
| 779 |
Megalencephaly-Capillary Malformation
|
nord_779_5
|
Diagnosis of Megalencephaly-Capillary Malformation
|
A diagnosis of macrocephaly-capillary malformation may be confirmed through a thorough clinical evaluation that includes a detailed history and physical examination looking for MCAP-associated features. Molecular diagnosis requires demonstration of a mosaic activating mutation in PIK3CA, which may require advanced genetic testing to be performed on affected tissues (e.g., skin fibroblasts) or samples other than blood. Different diagnostic criteria have been proposed in the medial literature.Clinical Testing and Work-UpBrain Imaging techniques such as magnetic resonance imaging (MRI) is recommended for all children with megalencephaly overall, and features of MCAP syndrome specifically. Furthermore, given the potential complications in MCAP (hydrocephalus and cerebellar tonsillar herniation), frequent MRI monitoring is recommended. While no standard recommendations exist regarding the frequency of imaging, an MRI scan every 6 months until 2-3 years of age may be reasonable. More frequent imaging maybe recommended if there are concerning signs or symptoms (such as very rapidly enlarging head size, rapidly progressive hydrocephalus and/or cerebellar tonsillar ectopia).
|
Diagnosis of Megalencephaly-Capillary Malformation. A diagnosis of macrocephaly-capillary malformation may be confirmed through a thorough clinical evaluation that includes a detailed history and physical examination looking for MCAP-associated features. Molecular diagnosis requires demonstration of a mosaic activating mutation in PIK3CA, which may require advanced genetic testing to be performed on affected tissues (e.g., skin fibroblasts) or samples other than blood. Different diagnostic criteria have been proposed in the medial literature.Clinical Testing and Work-UpBrain Imaging techniques such as magnetic resonance imaging (MRI) is recommended for all children with megalencephaly overall, and features of MCAP syndrome specifically. Furthermore, given the potential complications in MCAP (hydrocephalus and cerebellar tonsillar herniation), frequent MRI monitoring is recommended. While no standard recommendations exist regarding the frequency of imaging, an MRI scan every 6 months until 2-3 years of age may be reasonable. More frequent imaging maybe recommended if there are concerning signs or symptoms (such as very rapidly enlarging head size, rapidly progressive hydrocephalus and/or cerebellar tonsillar ectopia).
| 779 |
Megalencephaly-Capillary Malformation
|
nord_779_6
|
Therapies of Megalencephaly-Capillary Malformation
|
Treatment and surveillance of a child affected with MCAP may require the coordinated efforts of a team of specialists including a pediatrician, neurologist, developmental specialists, orthopedic surgeon, ophthalmologist, and, in some cases, neurosurgeon, dermatologist and other healthcare professionals who may need to systematically and comprehensively plan an affected child’s treatment.Treatment will vary depending upon many factors including the presence and severity of specific abnormalities; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.Hydrocephalus and cerebellar tonsillar ectopia warrant immediate attention and referral to a neurosurgeon. Rapidly progressive hydrocephalus may require neurosurgical shunting, and experience suggests that some patients benefit from a minimally-invasive 4th ventriculostomy. The guidelines for the management of cerebellar tonsillar ectopia are less clear. However surgical management (posterior fossa decompression) should be considered on a case-by-case basis and discussed with the neurologist and neurosurgeon involved in the child’s care. Seizures, if present, should be managed by a neurologist.The vascular anomalies associated with MCAP, especially if few or small, may fade or disappear without treatment (i.e., undergo spontaneous remission) within the first few years of life. Some patients have undergone laser ablation therapy for lesions depending on their size, location and extent. The appropriate management of these vascular anomalies should therefore be discussed with child’s caring physicians.Other therapies may include physiotherapy and occupational therapy as appropriate, and special education services.
|
Therapies of Megalencephaly-Capillary Malformation. Treatment and surveillance of a child affected with MCAP may require the coordinated efforts of a team of specialists including a pediatrician, neurologist, developmental specialists, orthopedic surgeon, ophthalmologist, and, in some cases, neurosurgeon, dermatologist and other healthcare professionals who may need to systematically and comprehensively plan an affected child’s treatment.Treatment will vary depending upon many factors including the presence and severity of specific abnormalities; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.Hydrocephalus and cerebellar tonsillar ectopia warrant immediate attention and referral to a neurosurgeon. Rapidly progressive hydrocephalus may require neurosurgical shunting, and experience suggests that some patients benefit from a minimally-invasive 4th ventriculostomy. The guidelines for the management of cerebellar tonsillar ectopia are less clear. However surgical management (posterior fossa decompression) should be considered on a case-by-case basis and discussed with the neurologist and neurosurgeon involved in the child’s care. Seizures, if present, should be managed by a neurologist.The vascular anomalies associated with MCAP, especially if few or small, may fade or disappear without treatment (i.e., undergo spontaneous remission) within the first few years of life. Some patients have undergone laser ablation therapy for lesions depending on their size, location and extent. The appropriate management of these vascular anomalies should therefore be discussed with child’s caring physicians.Other therapies may include physiotherapy and occupational therapy as appropriate, and special education services.
| 779 |
Megalencephaly-Capillary Malformation
|
nord_780_0
|
Overview of Megaloblastic Anemia
|
Megaloblastic anemia is characterized by unusually large, structurally abnormal blood cells (megaloblasts) that do not function normally. Bone marrow, the soft spongy material found inside certain bones, produces the main blood cells of the body – red blood cells, white blood cells and platelets. All three cell lines may be affected in megaloblastic anemia. Anemia is a condition characterized by low levels of circulating red blood cells. Red blood cells are released from the marrow into the bloodstream where they travel throughout the body delivering oxygen to tissue. A deficiency in healthy, fully-matured red blood cells can result in fatigue, paleness of the skin (pallor), lightheadedness and additional findings. Megaloblastic anemia has several different causes – deficiencies of either cobalamin (vitamin B12) or folate (vitamin B9) are the two most common causes; dihydrofolate reductase deficiency is another more uncommon cause. Vitamin B12 and vitamin B9 play an essential role in the production of red blood cells. This disease can be diagnosed based on laboratory tests or characteristic findings when tissue is viewed under microscope.
|
Overview of Megaloblastic Anemia. Megaloblastic anemia is characterized by unusually large, structurally abnormal blood cells (megaloblasts) that do not function normally. Bone marrow, the soft spongy material found inside certain bones, produces the main blood cells of the body – red blood cells, white blood cells and platelets. All three cell lines may be affected in megaloblastic anemia. Anemia is a condition characterized by low levels of circulating red blood cells. Red blood cells are released from the marrow into the bloodstream where they travel throughout the body delivering oxygen to tissue. A deficiency in healthy, fully-matured red blood cells can result in fatigue, paleness of the skin (pallor), lightheadedness and additional findings. Megaloblastic anemia has several different causes – deficiencies of either cobalamin (vitamin B12) or folate (vitamin B9) are the two most common causes; dihydrofolate reductase deficiency is another more uncommon cause. Vitamin B12 and vitamin B9 play an essential role in the production of red blood cells. This disease can be diagnosed based on laboratory tests or characteristic findings when tissue is viewed under microscope.
| 780 |
Megaloblastic Anemia
|
nord_780_1
|
Symptoms of Megaloblastic Anemia
|
In most patients, megaloblastic anemia develops slowly, and affected individuals may not have any apparent symptoms (asymptomatic) for many years. Symptoms common to anemia usually develop at some point and may include fatigue, paleness of the skin (pallor), shortness of breath, lightheadedness, dizziness and a fast or irregular heartbeat. The specific symptoms present in each individual can vary greatly. Additional common symptoms include aches and pains, muscle weakness and difficulty
breathing (dyspnea). Individuals with megaloblastic anemia may also develop gastrointestinal abnormalities including diarrhea, nausea and loss of appetite. Some affected individuals may develop a sore, reddened tongue. These abnormalities may result in unintended weight loss. Mild enlargement of the liver (hepatomegaly) and a slight yellowing of the skin or eyes (jaundice) may also occur.Megaloblastic anemia resulting from cobalamin deficiency may also be associated with neurological symptoms, presenting as tingling or numbness in the hands or feet. Additional symptoms develop over time including balance or gait problems, vision loss due to degeneration (atrophy) of the nerve that transmits impulses from the retina to the brain (optic nerve) and mental confusion or memory loss. A variety of psychiatric abnormalities have also been reported in individuals with cobalamin deficiency including depression, insomnia, listlessness and panic attacks. The spectrum of potential neuropsychological symptoms associated with cobalamin deficiency is large and varied. In rare cases of cobalamin deficiency, neurological symptoms may occur before the characteristic findings of anemia. Folate deficiency is generally considered not to result in neurological symptoms, although some recent research suggests that, in rare cases, it may cause some neurological symptoms.Symptoms of megaloblastic anemia due to dihydrofolate reductase deficiency are currently under investigation. The onset of symptoms for this type of megaloblastic anemia may start to appear in infants (1-23 months) and young children (2-11 years).
|
Symptoms of Megaloblastic Anemia. In most patients, megaloblastic anemia develops slowly, and affected individuals may not have any apparent symptoms (asymptomatic) for many years. Symptoms common to anemia usually develop at some point and may include fatigue, paleness of the skin (pallor), shortness of breath, lightheadedness, dizziness and a fast or irregular heartbeat. The specific symptoms present in each individual can vary greatly. Additional common symptoms include aches and pains, muscle weakness and difficulty
breathing (dyspnea). Individuals with megaloblastic anemia may also develop gastrointestinal abnormalities including diarrhea, nausea and loss of appetite. Some affected individuals may develop a sore, reddened tongue. These abnormalities may result in unintended weight loss. Mild enlargement of the liver (hepatomegaly) and a slight yellowing of the skin or eyes (jaundice) may also occur.Megaloblastic anemia resulting from cobalamin deficiency may also be associated with neurological symptoms, presenting as tingling or numbness in the hands or feet. Additional symptoms develop over time including balance or gait problems, vision loss due to degeneration (atrophy) of the nerve that transmits impulses from the retina to the brain (optic nerve) and mental confusion or memory loss. A variety of psychiatric abnormalities have also been reported in individuals with cobalamin deficiency including depression, insomnia, listlessness and panic attacks. The spectrum of potential neuropsychological symptoms associated with cobalamin deficiency is large and varied. In rare cases of cobalamin deficiency, neurological symptoms may occur before the characteristic findings of anemia. Folate deficiency is generally considered not to result in neurological symptoms, although some recent research suggests that, in rare cases, it may cause some neurological symptoms.Symptoms of megaloblastic anemia due to dihydrofolate reductase deficiency are currently under investigation. The onset of symptoms for this type of megaloblastic anemia may start to appear in infants (1-23 months) and young children (2-11 years).
| 780 |
Megaloblastic Anemia
|
nord_780_2
|
Causes of Megaloblastic Anemia
|
The most common causes of megaloblastic anemia are deficiency of either cobalamin (vitamin B12) or folate (vitamin B9). These two vitamins serve as building blocks and are essential for the production of healthy cells such as the precursors to red blood cells. Without these essential vitamins, the creation (synthesis) of deoxyribonucleic acid (DNA), the genetic material found in all cells, is hampered. Megaloblastic anemia may result from inadequate folate in the diet, from poor absorption of cobalamin by the intestines or improper utilization of these vitamins by the body. Folate deficiency has become rare because many countries supplement certain foods with folate. Most often, folate deficiency occurs in patients with severe malnutrition. Folate is found in green leafy vegetables, citrus fruits, certain grains and nuts, meat and liver. Folate deficiency can occur in diets without enough of these foods or due to decreased intake caused by an alcohol use disorder or malnutrition. Alcoholics may develop folate deficiency because alcohol does not contain folate and may impair the breakdown (metabolism) of folate in the body. Malabsorption of folate may occur in patients following gastric bypass surgery or patients with generalized inflammation of the bowel (for example those with celiac disease). Folate deficiency may result from conditions which use up or require increased amounts of folate, such as chronic eczema or hemolytic anemia. People who are pregnant or breastfeeding and individuals undergoing hemodialysis for kidney disease all have higher-than-normal demands for folate. Failure to adequately supplement folate in these individuals can potentially result in folate deficiency. Cobalamin is found in meat, fish, eggs and dairy products. Deficiency of cobalamin due to poor dietary intake is extremely rare but has occurred in people who eat a vegan diet. Cobalamin enters the body through a complex process involving the entire gastrointestinal tract. Normally, gastric parietal cells produce intrinsic factor (IF) which binds cobalamin in the gut. Unbound cobalamin is absorbed poorly and may be degraded during digestion. The IF-cobalamin complex courses down the intestines to the distal small bowel (ileum), where the most absorption of cobalamin occurs. Absorption of the IF-cobalamin complex occurs via specific receptors on enterocytes lining the ileum.Currently, almost all cobalamin deficiencies are caused by impaired absorption of the vitamin rather than dietary deficiencies. For example, impaired gastric function may lead to cobalamin deficiency because of deficient production of intrinsic factor (IF). Structural or functional disorders of the small bowel may also lead to impaired absorption of IF-bound cobalamin by the small intestine. Malabsorption may also result from surgery that leads to shortening or removal of the ileum, intestinal diseases such as Crohn’s disease or tropical sprue, or infection in the gastrointestinal tract. Pernicious anemia – a chronic autoimmune inflammatory disorder leading to gastric atrophy – may also cause cobalamin deficiency. This form of anemia is characterized by a lack of intrinsic factor, a protein that binds with cobalamin and aids in its absorption by the small intestine. Without enough intrinsic factor, the body cannot absorb enough cobalamin. Much rarer causes of megaloblastic anemia (unrelated to vitamin deficiency) have been identified including rare enzyme deficiencies known as inborn errors of metabolism and primary bone marrow disorders including myelodysplastic syndromes and acute myeloid leukemia. Small bowel absorption of cobalamin may also be caused by inherited changes in genes (called variants or mutations) that make proteins involved in the absorption of IF-cobalamin complex in the ileum. Imerslund-Graesbeck syndrome is a rare, autosomal recessive disorder usually diagnosed in infancy or early childhood, characterized by megaloblastic anemia and often associated with increased protein loss in the urine.Dihydrofolate reductase deficiency is a genetic disease caused by variants in the DHFR gene that can result in megaloblastic anemia.Thiamine-responsive megaloblastic anemia syndrome (TRMA) is a genetic disease caused by variants in the SLC19A2 gene that can result in megaloblastic anemia, diabetes mellitus and early-onset hearing loss. Certain medications can impair the body’s ability to absorb folate including many drugs used to treat cancer or anticonvulsants. Medications can also impair the synthesis of DNA resulting in megaloblastic anemia. In some people, bacteria may compete with the body for cobalamin as in blind loop syndrome, a disorder in which obstruction of the small intestines results in the abnormal buildup of bacteria in the gastrointestinal tract.In rare cases, a fish tapeworm known as Diphyllobothrium latum may take root in the small intestine and use up cobalamin, thereby depriving the body of necessary amounts of this essential vitamin. In some people the cause of megaloblastic anemia is unknown.
|
Causes of Megaloblastic Anemia. The most common causes of megaloblastic anemia are deficiency of either cobalamin (vitamin B12) or folate (vitamin B9). These two vitamins serve as building blocks and are essential for the production of healthy cells such as the precursors to red blood cells. Without these essential vitamins, the creation (synthesis) of deoxyribonucleic acid (DNA), the genetic material found in all cells, is hampered. Megaloblastic anemia may result from inadequate folate in the diet, from poor absorption of cobalamin by the intestines or improper utilization of these vitamins by the body. Folate deficiency has become rare because many countries supplement certain foods with folate. Most often, folate deficiency occurs in patients with severe malnutrition. Folate is found in green leafy vegetables, citrus fruits, certain grains and nuts, meat and liver. Folate deficiency can occur in diets without enough of these foods or due to decreased intake caused by an alcohol use disorder or malnutrition. Alcoholics may develop folate deficiency because alcohol does not contain folate and may impair the breakdown (metabolism) of folate in the body. Malabsorption of folate may occur in patients following gastric bypass surgery or patients with generalized inflammation of the bowel (for example those with celiac disease). Folate deficiency may result from conditions which use up or require increased amounts of folate, such as chronic eczema or hemolytic anemia. People who are pregnant or breastfeeding and individuals undergoing hemodialysis for kidney disease all have higher-than-normal demands for folate. Failure to adequately supplement folate in these individuals can potentially result in folate deficiency. Cobalamin is found in meat, fish, eggs and dairy products. Deficiency of cobalamin due to poor dietary intake is extremely rare but has occurred in people who eat a vegan diet. Cobalamin enters the body through a complex process involving the entire gastrointestinal tract. Normally, gastric parietal cells produce intrinsic factor (IF) which binds cobalamin in the gut. Unbound cobalamin is absorbed poorly and may be degraded during digestion. The IF-cobalamin complex courses down the intestines to the distal small bowel (ileum), where the most absorption of cobalamin occurs. Absorption of the IF-cobalamin complex occurs via specific receptors on enterocytes lining the ileum.Currently, almost all cobalamin deficiencies are caused by impaired absorption of the vitamin rather than dietary deficiencies. For example, impaired gastric function may lead to cobalamin deficiency because of deficient production of intrinsic factor (IF). Structural or functional disorders of the small bowel may also lead to impaired absorption of IF-bound cobalamin by the small intestine. Malabsorption may also result from surgery that leads to shortening or removal of the ileum, intestinal diseases such as Crohn’s disease or tropical sprue, or infection in the gastrointestinal tract. Pernicious anemia – a chronic autoimmune inflammatory disorder leading to gastric atrophy – may also cause cobalamin deficiency. This form of anemia is characterized by a lack of intrinsic factor, a protein that binds with cobalamin and aids in its absorption by the small intestine. Without enough intrinsic factor, the body cannot absorb enough cobalamin. Much rarer causes of megaloblastic anemia (unrelated to vitamin deficiency) have been identified including rare enzyme deficiencies known as inborn errors of metabolism and primary bone marrow disorders including myelodysplastic syndromes and acute myeloid leukemia. Small bowel absorption of cobalamin may also be caused by inherited changes in genes (called variants or mutations) that make proteins involved in the absorption of IF-cobalamin complex in the ileum. Imerslund-Graesbeck syndrome is a rare, autosomal recessive disorder usually diagnosed in infancy or early childhood, characterized by megaloblastic anemia and often associated with increased protein loss in the urine.Dihydrofolate reductase deficiency is a genetic disease caused by variants in the DHFR gene that can result in megaloblastic anemia.Thiamine-responsive megaloblastic anemia syndrome (TRMA) is a genetic disease caused by variants in the SLC19A2 gene that can result in megaloblastic anemia, diabetes mellitus and early-onset hearing loss. Certain medications can impair the body’s ability to absorb folate including many drugs used to treat cancer or anticonvulsants. Medications can also impair the synthesis of DNA resulting in megaloblastic anemia. In some people, bacteria may compete with the body for cobalamin as in blind loop syndrome, a disorder in which obstruction of the small intestines results in the abnormal buildup of bacteria in the gastrointestinal tract.In rare cases, a fish tapeworm known as Diphyllobothrium latum may take root in the small intestine and use up cobalamin, thereby depriving the body of necessary amounts of this essential vitamin. In some people the cause of megaloblastic anemia is unknown.
| 780 |
Megaloblastic Anemia
|
nord_780_3
|
Affects of Megaloblastic Anemia
|
Megaloblastic anemia affects males and females in equal numbers. It can occur in individuals of any racial or ethnic background. Because the causes of megaloblastic anemia vary and because some individuals may not exhibit any obvious symptoms, determining its true frequency in the general population is difficult. It is estimated that there are less than 1,000 people in the U.S. with the disease.
|
Affects of Megaloblastic Anemia. Megaloblastic anemia affects males and females in equal numbers. It can occur in individuals of any racial or ethnic background. Because the causes of megaloblastic anemia vary and because some individuals may not exhibit any obvious symptoms, determining its true frequency in the general population is difficult. It is estimated that there are less than 1,000 people in the U.S. with the disease.
| 780 |
Megaloblastic Anemia
|
nord_780_4
|
Related disorders of Megaloblastic Anemia
|
Symptoms of the following disorders can be similar to those of megaloblastic anemia. Comparisons may be useful for a differential diagnosis. Pernicious anemia is a blood disorder characterized by the inability of the body to properly utilize cobalamin (vitamin B12). Most cases result from the lack of the gastric protein known as intrinsic factor, without which vitamin B12 cannot be absorbed. The symptoms of pernicious anemia may include weakness, fatigue, upset stomach, abnormally rapid heartbeat (tachycardia) and/or chest pains. Recurring episodes of megaloblastic anemia and abnormal yellow coloration of the skin (jaundice) are also common. Pernicious anemia is thought to be an autoimmune disorder, and certain people may have a genetic predisposition to this disorder. There is a rare congenital form of pernicious anemia in which babies are born lacking the ability to produce effective intrinsic factors. There is also a juvenile form of the disease, but pernicious anemia typically does not appear before the age of 30. The onset of the disease is slow and may span decades. When the disease goes undiagnosed and untreated for a long period of time, it may lead to neurological complications. In some people, the structural changes in megaloblasts that characterize megaloblastic anemia have been mistaken for certain primary bone marrow disorders such as acute myeloid leukemia, myelodysplastic syndromes and aplastic anemia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
|
Related disorders of Megaloblastic Anemia. Symptoms of the following disorders can be similar to those of megaloblastic anemia. Comparisons may be useful for a differential diagnosis. Pernicious anemia is a blood disorder characterized by the inability of the body to properly utilize cobalamin (vitamin B12). Most cases result from the lack of the gastric protein known as intrinsic factor, without which vitamin B12 cannot be absorbed. The symptoms of pernicious anemia may include weakness, fatigue, upset stomach, abnormally rapid heartbeat (tachycardia) and/or chest pains. Recurring episodes of megaloblastic anemia and abnormal yellow coloration of the skin (jaundice) are also common. Pernicious anemia is thought to be an autoimmune disorder, and certain people may have a genetic predisposition to this disorder. There is a rare congenital form of pernicious anemia in which babies are born lacking the ability to produce effective intrinsic factors. There is also a juvenile form of the disease, but pernicious anemia typically does not appear before the age of 30. The onset of the disease is slow and may span decades. When the disease goes undiagnosed and untreated for a long period of time, it may lead to neurological complications. In some people, the structural changes in megaloblasts that characterize megaloblastic anemia have been mistaken for certain primary bone marrow disorders such as acute myeloid leukemia, myelodysplastic syndromes and aplastic anemia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
| 780 |
Megaloblastic Anemia
|
nord_780_5
|
Diagnosis of Megaloblastic Anemia
|
A diagnosis of megaloblastic anemia is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of blood tests. Blood tests may reveal the abnormally large, misshapen red blood cells that characterize megaloblastic anemia. Blood tests can also confirm cobalamin or folate deficiency as the cause of megaloblastic anemia. Additional tests such as a Schilling test, which confirms poor absorption as the cause of cobalamin deficiency, may be necessary. Patients should be evaluated for the underlying conditions that can lead to megaloblastic anemia. Patients with progressive sensorineural hearing loss and diabetes mellitus in addition to megaloblastic anemia should be tested for thiamine-responsive megaloblastic anemia syndrome (TRMA). Molecular genetic testing for variants in the SLC19A2 gene or genomic sequencing can confirm this diagnosis.
|
Diagnosis of Megaloblastic Anemia. A diagnosis of megaloblastic anemia is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of blood tests. Blood tests may reveal the abnormally large, misshapen red blood cells that characterize megaloblastic anemia. Blood tests can also confirm cobalamin or folate deficiency as the cause of megaloblastic anemia. Additional tests such as a Schilling test, which confirms poor absorption as the cause of cobalamin deficiency, may be necessary. Patients should be evaluated for the underlying conditions that can lead to megaloblastic anemia. Patients with progressive sensorineural hearing loss and diabetes mellitus in addition to megaloblastic anemia should be tested for thiamine-responsive megaloblastic anemia syndrome (TRMA). Molecular genetic testing for variants in the SLC19A2 gene or genomic sequencing can confirm this diagnosis.
| 780 |
Megaloblastic Anemia
|
nord_780_6
|
Therapies of Megaloblastic Anemia
|
Treatment
The treatment of megaloblastic anemia depends upon the underlying cause of the disorder. Dietary insufficiency of cobalamin and folate can be treated with appropriate changes to the diet and diet supplements. In individuals who cannot absorb cobalamin or folate properly, life-long vitamin supplements may be necessary. Prompt treatment of cobalamin deficiency is important because of the risk of neurological symptoms. In patients with deficiency in both cobalamin and folate, replenishing cobalamin should be the first priority in order to avoid degeneration of the spinal cord. If underlying disorders (e.g., Crohn's disease, tropical sprue, celiac sprue, blind loop syndrome, inborn errors of metabolism) are the cause of these vitamin deficiencies, appropriate treatment for the specific disorder is required. Supplementation with either cobalamin or folate may also be required.If medications are the cause of vitamin deficiency, use of the medication should be stopped, or the dosage lowered.In certain patients, such as those with thiamine-responsive megaloblastic anemia syndrome (TRMA), megaloblastic anemia can be treated with oral thiamine. Hearing loss cannot be reversed by thiamine treatment. Red blood cell transfusion may be used for severe cases of anemia. Preventive (prophylactic) folate supplementation may be recommended for individuals who have higher-than-normal demands for folate such as people who are pregnant.
|
Therapies of Megaloblastic Anemia. Treatment
The treatment of megaloblastic anemia depends upon the underlying cause of the disorder. Dietary insufficiency of cobalamin and folate can be treated with appropriate changes to the diet and diet supplements. In individuals who cannot absorb cobalamin or folate properly, life-long vitamin supplements may be necessary. Prompt treatment of cobalamin deficiency is important because of the risk of neurological symptoms. In patients with deficiency in both cobalamin and folate, replenishing cobalamin should be the first priority in order to avoid degeneration of the spinal cord. If underlying disorders (e.g., Crohn's disease, tropical sprue, celiac sprue, blind loop syndrome, inborn errors of metabolism) are the cause of these vitamin deficiencies, appropriate treatment for the specific disorder is required. Supplementation with either cobalamin or folate may also be required.If medications are the cause of vitamin deficiency, use of the medication should be stopped, or the dosage lowered.In certain patients, such as those with thiamine-responsive megaloblastic anemia syndrome (TRMA), megaloblastic anemia can be treated with oral thiamine. Hearing loss cannot be reversed by thiamine treatment. Red blood cell transfusion may be used for severe cases of anemia. Preventive (prophylactic) folate supplementation may be recommended for individuals who have higher-than-normal demands for folate such as people who are pregnant.
| 780 |
Megaloblastic Anemia
|
nord_781_0
|
Overview of Megalocornea Intellectual Disability Syndrome
|
Megalocornea-intellectual disability syndrome is an extremely rare disorder that is characterized by distinctive abnormalities of the cornea of the eye (megalocornea) and varying degrees of cognitive impairment (intellectual disability). Most patients also present with diminished muscle tone (hypotonia) and may experience a wide variety of additional symptoms that can vary in severity. Individuals are typically diagnosed during early infancy or early childhood. To date, there have been approximately 40 individuals reported with megalocornea-intellectual disability syndrome in the medical literature. While the exact cause of this condition is unknown, it is suspected to have a genetic basis.
|
Overview of Megalocornea Intellectual Disability Syndrome. Megalocornea-intellectual disability syndrome is an extremely rare disorder that is characterized by distinctive abnormalities of the cornea of the eye (megalocornea) and varying degrees of cognitive impairment (intellectual disability). Most patients also present with diminished muscle tone (hypotonia) and may experience a wide variety of additional symptoms that can vary in severity. Individuals are typically diagnosed during early infancy or early childhood. To date, there have been approximately 40 individuals reported with megalocornea-intellectual disability syndrome in the medical literature. While the exact cause of this condition is unknown, it is suspected to have a genetic basis.
| 781 |
Megalocornea Intellectual Disability Syndrome
|
nord_781_1
|
Symptoms of Megalocornea Intellectual Disability Syndrome
|
A characteristic symptom of all individuals affected with megalocornea-intellectual disability syndrome is a distinctive eye abnormality known as megalocornea, which is the abnormal, nonprogressive enlargement of the cornea that occurs without the presence of increased pressure within the eye (glaucoma). The cornea is the clear (transparent) outer layer of the eye and has two functions – it protects the rest of the eye from dust, germs and other harmful or irritating material and it acts as the eye’s outermost lens, bending incoming light onto the inner lens, where the light is then directed to the retina (a membranous layer of light-sensing cells in the back of the eye). The retina converts light to images, which are then transmitted to the brain. The cornea must remain clear to be able to focus incoming light. Megalocornea is present at birth (congenital) and usually affects both eyes (bilateral). Although the cornea is abnormally enlarged, it is otherwise normal in structure, curvature and thickness. Some affected individuals have additional abnormalities affecting the eyes including underdevelopment (hypoplasia) of the colored portion of the eyes (iris), abnormal “unsteadiness” of the irises during eye movements (iridodonesis) and abnormal shaping of the eye so that it does not bend light appropriately (refractive errors).These additional eye abnormalities can potentially lead to varying degrees of visual impairment.Other characteristic features of all individuals affected with this condition include intellectual disability and delays in the acquisition of motor skills (psychomotor delay). Most (>80%) affected individuals also experience hypotonia. Other neurologic abnormalities may be observed, including delayed speech development, poor coordination and clumsiness, seizures, hyperactivity and involuntary movements of the face, arms and legs (limbs) and trunk consisting of slow, continual, writhing movements (athetosis) occurring in association with more rapid, jerky movements (choreoathetoid movements).Individuals with megalocornea-intellectual disability syndrome may also have distinctive features in the head and face area (craniofacial region). These include microcephaly, a condition that indicates that the head circumference is smaller than would be expected for an infant’s age and sex, or macrocephaly, a condition in which there is a disproportionally large head circumference. Additional craniofacial findings may include an unusually prominent forehead (frontal bossing), widely spaced eyes (ocular hypertelorism), downward slanting eyelid folds (palpebral fissures), vertical skin folds between the inner corners of the eyes and the nose (epicanthal folds), widening of the top part of the nose (broad nasal bridge), a long upper lip, an abnormally small lower jaw (micrognathia), a high and narrow roof of the mouth (high arched palate) and/or unusually large and/or “cup-shaped” ears.Rare physical malformations may also be present, including abnormally long and/or permanently flexed fingers (camptodactyly), abnormal sideways curvature of the spine (scoliosis), abnormal forward curvature of the spine (kyphosis) and heart defects. Patients have also been reported with very flexible joints (joint hyperlaxity). Additionally, affected individuals may experience primary hypothyroidism where the thyroid gland does not produce appropriate levels of hormones. These hormones are required for many bodily functions including growth and metabolism. Some affected individuals experience growth delays ultimately resulting in short stature. Recurrent infections have also been reported in some patients.
|
Symptoms of Megalocornea Intellectual Disability Syndrome. A characteristic symptom of all individuals affected with megalocornea-intellectual disability syndrome is a distinctive eye abnormality known as megalocornea, which is the abnormal, nonprogressive enlargement of the cornea that occurs without the presence of increased pressure within the eye (glaucoma). The cornea is the clear (transparent) outer layer of the eye and has two functions – it protects the rest of the eye from dust, germs and other harmful or irritating material and it acts as the eye’s outermost lens, bending incoming light onto the inner lens, where the light is then directed to the retina (a membranous layer of light-sensing cells in the back of the eye). The retina converts light to images, which are then transmitted to the brain. The cornea must remain clear to be able to focus incoming light. Megalocornea is present at birth (congenital) and usually affects both eyes (bilateral). Although the cornea is abnormally enlarged, it is otherwise normal in structure, curvature and thickness. Some affected individuals have additional abnormalities affecting the eyes including underdevelopment (hypoplasia) of the colored portion of the eyes (iris), abnormal “unsteadiness” of the irises during eye movements (iridodonesis) and abnormal shaping of the eye so that it does not bend light appropriately (refractive errors).These additional eye abnormalities can potentially lead to varying degrees of visual impairment.Other characteristic features of all individuals affected with this condition include intellectual disability and delays in the acquisition of motor skills (psychomotor delay). Most (>80%) affected individuals also experience hypotonia. Other neurologic abnormalities may be observed, including delayed speech development, poor coordination and clumsiness, seizures, hyperactivity and involuntary movements of the face, arms and legs (limbs) and trunk consisting of slow, continual, writhing movements (athetosis) occurring in association with more rapid, jerky movements (choreoathetoid movements).Individuals with megalocornea-intellectual disability syndrome may also have distinctive features in the head and face area (craniofacial region). These include microcephaly, a condition that indicates that the head circumference is smaller than would be expected for an infant’s age and sex, or macrocephaly, a condition in which there is a disproportionally large head circumference. Additional craniofacial findings may include an unusually prominent forehead (frontal bossing), widely spaced eyes (ocular hypertelorism), downward slanting eyelid folds (palpebral fissures), vertical skin folds between the inner corners of the eyes and the nose (epicanthal folds), widening of the top part of the nose (broad nasal bridge), a long upper lip, an abnormally small lower jaw (micrognathia), a high and narrow roof of the mouth (high arched palate) and/or unusually large and/or “cup-shaped” ears.Rare physical malformations may also be present, including abnormally long and/or permanently flexed fingers (camptodactyly), abnormal sideways curvature of the spine (scoliosis), abnormal forward curvature of the spine (kyphosis) and heart defects. Patients have also been reported with very flexible joints (joint hyperlaxity). Additionally, affected individuals may experience primary hypothyroidism where the thyroid gland does not produce appropriate levels of hormones. These hormones are required for many bodily functions including growth and metabolism. Some affected individuals experience growth delays ultimately resulting in short stature. Recurrent infections have also been reported in some patients.
| 781 |
Megalocornea Intellectual Disability Syndrome
|
nord_781_2
|
Causes of Megalocornea Intellectual Disability Syndrome
|
The exact cause of megalocornea-intellectual disability syndrome is unknown. However, cases reported in the literature are consistent with an autosomal recessive inheritance pattern or new (de novo) genetic changes (variants) that were not inherited from parents.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. Although megalocornea intellectual disability syndrome is suspected to have an underlying genetic cause, genetic variants in specific genes have not been shown to cause the condition.
|
Causes of Megalocornea Intellectual Disability Syndrome. The exact cause of megalocornea-intellectual disability syndrome is unknown. However, cases reported in the literature are consistent with an autosomal recessive inheritance pattern or new (de novo) genetic changes (variants) that were not inherited from parents.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. Although megalocornea intellectual disability syndrome is suspected to have an underlying genetic cause, genetic variants in specific genes have not been shown to cause the condition.
| 781 |
Megalocornea Intellectual Disability Syndrome
|
nord_781_3
|
Affects of Megalocornea Intellectual Disability Syndrome
|
Megalocornea-intellectual disability syndrome is typically diagnosed in early childhood or early infancy. Due to the rarity of the condition and the small number of documented cases, there are no accurate estimates for the incidence of this condition. To date, approximately 40 individuals with the condition have been reported in the medical literature. Most are sporadic, meaning that individuals are typically the only ones affected with the condition in their families. An approximately equal number of males and females have been reported. Additionally, individuals across varied races have been reported with this condition.
|
Affects of Megalocornea Intellectual Disability Syndrome. Megalocornea-intellectual disability syndrome is typically diagnosed in early childhood or early infancy. Due to the rarity of the condition and the small number of documented cases, there are no accurate estimates for the incidence of this condition. To date, approximately 40 individuals with the condition have been reported in the medical literature. Most are sporadic, meaning that individuals are typically the only ones affected with the condition in their families. An approximately equal number of males and females have been reported. Additionally, individuals across varied races have been reported with this condition.
| 781 |
Megalocornea Intellectual Disability Syndrome
|
nord_781_4
|
Related disorders of Megalocornea Intellectual Disability Syndrome
|
Symptoms of the following disorder can be similar to those of megalocornea-intellectual disability syndrome. Comparisons may be useful for a differential diagnosis.Frank Ter Haar syndrome is a rare inherited condition characterized by developmental delay, skeletal abnormalities such as short fingers or toes (brachydactyly) and bone death due to decreased blood supply (avascular necrosis) and other craniofacial features including megalocornea with or without glaucoma, a flattened back of the head, larger-than-expected soft spots between bony plates of the skull (wide fontanelles), frontal bossing, ocular hypertelorism, full cheeks and a small chin. Affected individuals may also have protruding ears, a prominent tail bone (coccyx bone), and heart defects present from birth. Frank Ter Haar syndrome is thought to follow a recessive inheritance pattern and is caused by genetic variants in the SH3PXD2B gene. There are less than 30 documented cases of this condition worldwide.There are a number of other disorders that may be characterized by abnormalities of the eyes, intellectual disability, hypotonia, psychomotor delay, craniofacial malformations and/or other abnormalities similar to those occurring in association with megalocornea-intellectual disability syndrome. These disorders usually have other physical features that may differentiate them from megalocornea-intellectual disability 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 Megalocornea Intellectual Disability Syndrome. Symptoms of the following disorder can be similar to those of megalocornea-intellectual disability syndrome. Comparisons may be useful for a differential diagnosis.Frank Ter Haar syndrome is a rare inherited condition characterized by developmental delay, skeletal abnormalities such as short fingers or toes (brachydactyly) and bone death due to decreased blood supply (avascular necrosis) and other craniofacial features including megalocornea with or without glaucoma, a flattened back of the head, larger-than-expected soft spots between bony plates of the skull (wide fontanelles), frontal bossing, ocular hypertelorism, full cheeks and a small chin. Affected individuals may also have protruding ears, a prominent tail bone (coccyx bone), and heart defects present from birth. Frank Ter Haar syndrome is thought to follow a recessive inheritance pattern and is caused by genetic variants in the SH3PXD2B gene. There are less than 30 documented cases of this condition worldwide.There are a number of other disorders that may be characterized by abnormalities of the eyes, intellectual disability, hypotonia, psychomotor delay, craniofacial malformations and/or other abnormalities similar to those occurring in association with megalocornea-intellectual disability syndrome. These disorders usually have other physical features that may differentiate them from megalocornea-intellectual disability syndrome. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)
| 781 |
Megalocornea Intellectual Disability Syndrome
|
nord_781_5
|
Diagnosis of Megalocornea Intellectual Disability Syndrome
|
Megalocornea-intellectual disability syndrome is diagnosed during early infancy or early childhood based on a clinical evaluation, identification of characteristic physical findings and/or a variety of specialized tests. Many researchers agree that the presence of megalocornea and intellectual disability should be considered the minimal criteria upon which to base a diagnosis. Signs and symptoms such as megalocornea, hypotonia and craniofacial abnormalities may be apparent at birth (congenital). However, certain abnormalities associated with the syndrome, such as intellectual disability, psychomotor delay and/or short stature, may not be confirmed until later during infancy or childhood.Specialized tests may be conducted to confirm the presence of certain abnormalities that may be associated with the syndrome. For example, thorough examination with or without general anesthesia may be conducted with an instrument that visualizes the interior of the eye (ophthalmoscopy) to detect, confirm and/or characterize megalocornea, iris hypoplasia and/or other ocular abnormalities potentially associated with the disorder. Additionally, in some affected infants and children, electroencephalography (EEG), which records the brain’s electrical impulses, may reveal epileptic activity. Advanced X-ray studies may be used to confirm craniofacial malformations (e.g., microcephaly or macrocephaly, frontal bossing, micrognathia) and/or skeletal abnormalities (e.g., camptodactyly, scoliosis, kyphosis) potentially associated with the disorder. Brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) scans may reveal structural brain malformations (such as cerebral atrophy, underdeveloped corpus callosum, delayed myelination, mild ventricular dilatation). In some affected individuals, ultrasound imaging of the heart with echocardiography may reveal heart defects.
|
Diagnosis of Megalocornea Intellectual Disability Syndrome. Megalocornea-intellectual disability syndrome is diagnosed during early infancy or early childhood based on a clinical evaluation, identification of characteristic physical findings and/or a variety of specialized tests. Many researchers agree that the presence of megalocornea and intellectual disability should be considered the minimal criteria upon which to base a diagnosis. Signs and symptoms such as megalocornea, hypotonia and craniofacial abnormalities may be apparent at birth (congenital). However, certain abnormalities associated with the syndrome, such as intellectual disability, psychomotor delay and/or short stature, may not be confirmed until later during infancy or childhood.Specialized tests may be conducted to confirm the presence of certain abnormalities that may be associated with the syndrome. For example, thorough examination with or without general anesthesia may be conducted with an instrument that visualizes the interior of the eye (ophthalmoscopy) to detect, confirm and/or characterize megalocornea, iris hypoplasia and/or other ocular abnormalities potentially associated with the disorder. Additionally, in some affected infants and children, electroencephalography (EEG), which records the brain’s electrical impulses, may reveal epileptic activity. Advanced X-ray studies may be used to confirm craniofacial malformations (e.g., microcephaly or macrocephaly, frontal bossing, micrognathia) and/or skeletal abnormalities (e.g., camptodactyly, scoliosis, kyphosis) potentially associated with the disorder. Brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) scans may reveal structural brain malformations (such as cerebral atrophy, underdeveloped corpus callosum, delayed myelination, mild ventricular dilatation). In some affected individuals, ultrasound imaging of the heart with echocardiography may reveal heart defects.
| 781 |
Megalocornea Intellectual Disability Syndrome
|
nord_781_6
|
Therapies of Megalocornea Intellectual Disability Syndrome
|
Treatment is directed towards the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physical therapists and specialists who assess and treat eye problems (ophthalmologists), neurological disorders (neurologists), skeletal disorders (orthopedists) and heart problems (cardiologists) may need to systematically and comprehensively plan an affected child’s treatment.In affected infants or children with megalocornea, iris abnormalities and/or refractive errors, corrective glasses, contact lenses, surgery and/or other supportive techniques may be used to help improve vision.In some affected infants and children with neuromuscular abnormalities, physical therapy and/or other supportive therapies may be used to help improve motor skills and coordination. In some patients, treatment with anticonvulsant drugs may help to prevent, reduce or control seizures potentially occurring in association with the disorder. In some patients, hormone replacement therapies can be initiated to treat hypothyroidism and normalize thyroid hormone levels.Early intervention is important to ensure that children with this syndrome reach their full potential. Special services that may be beneficial to affected children may include special education, special social support and other medical, social, and/or vocational services. Genetic counseling is recommended for affected individuals and their families.
|
Therapies of Megalocornea Intellectual Disability Syndrome. Treatment is directed towards the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physical therapists and specialists who assess and treat eye problems (ophthalmologists), neurological disorders (neurologists), skeletal disorders (orthopedists) and heart problems (cardiologists) may need to systematically and comprehensively plan an affected child’s treatment.In affected infants or children with megalocornea, iris abnormalities and/or refractive errors, corrective glasses, contact lenses, surgery and/or other supportive techniques may be used to help improve vision.In some affected infants and children with neuromuscular abnormalities, physical therapy and/or other supportive therapies may be used to help improve motor skills and coordination. In some patients, treatment with anticonvulsant drugs may help to prevent, reduce or control seizures potentially occurring in association with the disorder. In some patients, hormone replacement therapies can be initiated to treat hypothyroidism and normalize thyroid hormone levels.Early intervention is important to ensure that children with this syndrome reach their full potential. Special services that may be beneficial to affected children may include special education, special social support and other medical, social, and/or vocational services. Genetic counseling is recommended for affected individuals and their families.
| 781 |
Megalocornea Intellectual Disability Syndrome
|
nord_782_0
|
Overview of Meier-Gorlin Syndrome
|
Summary Meier-Gorlin syndrome (MGS) is a rare genetic disorder. The main features are small ears (microtia), absent or small kneecaps (patellae) and short stature. MGS should be considered in children with at least two of these three features.There are other features of MGS that may include various skeletal differences, early feeding difficulties and poor weight gain. In addition, unique features of the head and face may be present including a small mouth with full lips, small size of the head (microcephaly) and/or small jaw bones (micrognathia).People with MGS usually have normal intellectual ability and a normal lifespan.MGS is usually inherited in an autosomal recessive pattern but can be autosomal dominant in some families.IntroductionMGS was first reported by Meier in 1959 and Gorlin in 1975. Since then about 67 patients have been described with MGS.
|
Overview of Meier-Gorlin Syndrome. Summary Meier-Gorlin syndrome (MGS) is a rare genetic disorder. The main features are small ears (microtia), absent or small kneecaps (patellae) and short stature. MGS should be considered in children with at least two of these three features.There are other features of MGS that may include various skeletal differences, early feeding difficulties and poor weight gain. In addition, unique features of the head and face may be present including a small mouth with full lips, small size of the head (microcephaly) and/or small jaw bones (micrognathia).People with MGS usually have normal intellectual ability and a normal lifespan.MGS is usually inherited in an autosomal recessive pattern but can be autosomal dominant in some families.IntroductionMGS was first reported by Meier in 1959 and Gorlin in 1975. Since then about 67 patients have been described with MGS.
| 782 |
Meier-Gorlin Syndrome
|
nord_782_1
|
Symptoms of Meier-Gorlin Syndrome
|
The main clinical features of MGS are small ears, kneecap abnormalities and short stature. These features can be seen at birth and are discussed in more detail below. People with MGS can have small or absent outer ears (microtia). The ears can also be low-set and/or unusually formed. They may have narrower or absent ear canals which could affect their hearing. The kneecaps may be small or even missing. This may cause an unstable knee joint which could lead to chronic knee pain. Short stature is due, in part, to the slow growth that can occur before and after birth in babies with MGS. As a result, these babies have low birth weight and can have feeding difficulties that result in a slower development and short stature. This syndrome has a range of symptoms with severity anywhere from mild to severe. The following symptoms are associated with MGS, but not everyone diagnosed with MGS will have all of these symptoms. Skeletal Differences
People with MGS may have differences in their bone development. These may include slender, missing, or unusually shaped ribs with slender arm and leg bones. Elbows can be dislocated, collar bones can be hook-shaped and/or long bones can have flat ends. There have been some patients with an absent or abnormally shallow depression on the upper arm bone located where the bone meets the shoulder. There have also been patients with detachment of cartilage and bone tissue from the surface of a bone, unusually extended joints, and abnormally stiff joints that may lock in position. Specifically, hands can have the fifth finger be abnormally bent, and/or one or more fingers may be permanently flexed. Facial Features
In addition to those mentioned above, facial features can include a triangular face, an arched roof of the mouth and/or droopy eyelids. Facial features may include full lips and a narrow nose with a small jaw and mouth. Life Span
Most people with MGS have a normal life expectancy. The oldest documented adult is a 65-year-old woman. The lifespan of those with MGS may depend on the severity of the symptoms experienced by each person. Intellectual and Motor Development
Most people with MGS have normal intelligence and learning ability. Mental ability and motor coordination is normal or borderline normal. Some affected children show delays in attaining developmental and speech milestones. Growth
Growth after birth can be delayed during the first year of life with normal growth afterwards. However, due to this delay, people with MGS do not catch up to their peers and tend to be shorter in stature. Feeding
Feeding problems have been seen in the majority of those with MGS during infancy and young childhood. These problems can be due to acid reflux which may need further medical intervention such as medication. Respiratory
Likely due to their small stature, people with MGS can have breathing difficulties. Some report problems with releasing the air from their lungs, which will likely need medical intervention. Breathing difficulties can include coughing and wheezing due to weak lung structure. The weak structure and small size of the lungs can lead to recurrent infections in childhood. These infections tend to disappear after childhood. Sexual Development
In some boys with MGS, the testes may not descend into the scrotum (undescended testes). Some boys have an abnormal location of the urinary opening on the underside of the penis (hypospadias). Both of these concerns can be treated with surgery. Some girls with MGS may have underdeveloped breasts after reaching puberty. Some women with MGS have a small uterus. Some women with MGS have been reported to have many cysts on their ovaries. The impact of MGS on pregnancy is not well understood. However, there is a documented case of a woman with MGS having successful pregnancies, though the babies were born premature. Both males and females with MGS tend to have sparse or absent underarm hair while pubic hair growth is normal.
|
Symptoms of Meier-Gorlin Syndrome. The main clinical features of MGS are small ears, kneecap abnormalities and short stature. These features can be seen at birth and are discussed in more detail below. People with MGS can have small or absent outer ears (microtia). The ears can also be low-set and/or unusually formed. They may have narrower or absent ear canals which could affect their hearing. The kneecaps may be small or even missing. This may cause an unstable knee joint which could lead to chronic knee pain. Short stature is due, in part, to the slow growth that can occur before and after birth in babies with MGS. As a result, these babies have low birth weight and can have feeding difficulties that result in a slower development and short stature. This syndrome has a range of symptoms with severity anywhere from mild to severe. The following symptoms are associated with MGS, but not everyone diagnosed with MGS will have all of these symptoms. Skeletal Differences
People with MGS may have differences in their bone development. These may include slender, missing, or unusually shaped ribs with slender arm and leg bones. Elbows can be dislocated, collar bones can be hook-shaped and/or long bones can have flat ends. There have been some patients with an absent or abnormally shallow depression on the upper arm bone located where the bone meets the shoulder. There have also been patients with detachment of cartilage and bone tissue from the surface of a bone, unusually extended joints, and abnormally stiff joints that may lock in position. Specifically, hands can have the fifth finger be abnormally bent, and/or one or more fingers may be permanently flexed. Facial Features
In addition to those mentioned above, facial features can include a triangular face, an arched roof of the mouth and/or droopy eyelids. Facial features may include full lips and a narrow nose with a small jaw and mouth. Life Span
Most people with MGS have a normal life expectancy. The oldest documented adult is a 65-year-old woman. The lifespan of those with MGS may depend on the severity of the symptoms experienced by each person. Intellectual and Motor Development
Most people with MGS have normal intelligence and learning ability. Mental ability and motor coordination is normal or borderline normal. Some affected children show delays in attaining developmental and speech milestones. Growth
Growth after birth can be delayed during the first year of life with normal growth afterwards. However, due to this delay, people with MGS do not catch up to their peers and tend to be shorter in stature. Feeding
Feeding problems have been seen in the majority of those with MGS during infancy and young childhood. These problems can be due to acid reflux which may need further medical intervention such as medication. Respiratory
Likely due to their small stature, people with MGS can have breathing difficulties. Some report problems with releasing the air from their lungs, which will likely need medical intervention. Breathing difficulties can include coughing and wheezing due to weak lung structure. The weak structure and small size of the lungs can lead to recurrent infections in childhood. These infections tend to disappear after childhood. Sexual Development
In some boys with MGS, the testes may not descend into the scrotum (undescended testes). Some boys have an abnormal location of the urinary opening on the underside of the penis (hypospadias). Both of these concerns can be treated with surgery. Some girls with MGS may have underdeveloped breasts after reaching puberty. Some women with MGS have a small uterus. Some women with MGS have been reported to have many cysts on their ovaries. The impact of MGS on pregnancy is not well understood. However, there is a documented case of a woman with MGS having successful pregnancies, though the babies were born premature. Both males and females with MGS tend to have sparse or absent underarm hair while pubic hair growth is normal.
| 782 |
Meier-Gorlin Syndrome
|
nord_782_2
|
Causes of Meier-Gorlin Syndrome
|
MGS can be caused by changes (mutations) in eight different genes (ORC1, ORC4, ORC6, CDT1, CDC6, CDC45L, MCM5 and GMNN). Most forms of MGS are inherited in an autosomal recessive inheritance pattern. MGS type 6 (GMNN gene) is inherited in an autosomal dominant pattern. Recessive genetic conditions occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The 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. Recessive conditions are more common in people born to parents who are biologically related (consanguineous). 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 new gene change 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 Meier-Gorlin Syndrome. MGS can be caused by changes (mutations) in eight different genes (ORC1, ORC4, ORC6, CDT1, CDC6, CDC45L, MCM5 and GMNN). Most forms of MGS are inherited in an autosomal recessive inheritance pattern. MGS type 6 (GMNN gene) is inherited in an autosomal dominant pattern. Recessive genetic conditions occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The 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. Recessive conditions are more common in people born to parents who are biologically related (consanguineous). 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 new gene change 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.
| 782 |
Meier-Gorlin Syndrome
|
nord_782_3
|
Affects of Meier-Gorlin Syndrome
|
Since MGS was first described in 1959, only about 67 cases have been reported in the medical literature (Nov 2019). MGS is estimated to affect less than 1-9 individuals per 1,000,000 people. However, researchers believe this condition is under-diagnosed. MGS affects men and women equally.
|
Affects of Meier-Gorlin Syndrome. Since MGS was first described in 1959, only about 67 cases have been reported in the medical literature (Nov 2019). MGS is estimated to affect less than 1-9 individuals per 1,000,000 people. However, researchers believe this condition is under-diagnosed. MGS affects men and women equally.
| 782 |
Meier-Gorlin Syndrome
|
nord_782_4
|
Related disorders of Meier-Gorlin Syndrome
|
Symptoms of the following disorders can be similar to those of MGS. Looking at comparisons may be useful to clarify the diagnosis: Some researchers include MGS in a group of disorders known as primordial dwarfism. These disorders share similar features including skeletal abnormalities and lack of growth before birth and during infancy/childhood, ultimately resulting in short stature. This group of disorders includes five disorders: MGS; Seckel syndrome; Russell-Silver syndrome; and microcephalic osteodysplastic primordial dwarfism type 1 and 2. Russell-Silver syndrome is a rare genetic condition characterized by growth delays before birth, overgrowth of one side of the body, and unusual facial features. The range and severity of symptoms of Russell-Silver syndrome vary from person to person. The majority of those affected are of normal intelligence, but motor and/or speech delay is common. Growth delays before birth affect both weight and height. As such, affected infants may be small and have a low birth weight. In addition, growth delays and immature bone development continue after birth resulting in short stature. In most children, overgrowth of one side of the body is obvious at birth. This feature varies and may affect the head, trunk, arms, and/or legs. Facial features may include a triangular-shaped face with a small, pointed chin; a prominent forehead; bluish tint of the outer membranes covering the eyeballs; a small, wide mouth with downturned corners; and/or a small jaw. (For more information on this disorder, choose “Russell Silver syndrome” as your search term in the Rare Disease Database.) Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) is a genetic condition characterized by growth delays before and after birth, small head, skeletal abnormalities, distinctive facial features; and brain anomalies. Other signs and symptoms include sparse hair and eyebrows, dry skin, short limbs, dislocation of the hips and elbows, seizures; and intellectual disability.MOPD1 is caused by mutations in the RNU4ATAC gene and is inherited in an autosomal recessive manner. Microcephalic osteodysplastic primordial dwarfism type 2 (MOPD2) is an extremely rare genetic disorder. Features include short stature, a small head, and skeletal abnormalities. Other physical findings can be unusual skin color, blood vessel abnormalities, and/or a high-pitched voice. Severe growth deficiency before birth commonly occurs. Intellectual disability may be present in some children. Specific symptoms and severity vary from person to person. MOPD2 is caused by mutations in the PCNT gene and is inherited in an autosomal recessive fashion. Three M syndrome is an extremely rare genetic disorder with low birth weight, short stature, abnormalities of the head and face, distinctive skeletal defects, and/or other physical features. Intellectual ability is normal with this syndrome. Facial features typically include a long, narrow head, a prominent forehead, and a triangular-shaped face with a prominent, pointed chin, large ears, and/or abnormally flat cheeks. There are some patients reported to have abnormally crowded teeth. Skeletal abnormalities include very thin arm and leg bones; long, thin bones of the spinal column; and/or defects with the ribs and shoulder blades. Affected people may also have permanent fixation of certain fingers in a bent position, short fifth fingers, and/or highly flexible joints. The range and severity of symptoms and physical features may vary from person to person. Three M syndrome is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “three M syndrome” as your search term in the Rare Disease Database.)
|
Related disorders of Meier-Gorlin Syndrome. Symptoms of the following disorders can be similar to those of MGS. Looking at comparisons may be useful to clarify the diagnosis: Some researchers include MGS in a group of disorders known as primordial dwarfism. These disorders share similar features including skeletal abnormalities and lack of growth before birth and during infancy/childhood, ultimately resulting in short stature. This group of disorders includes five disorders: MGS; Seckel syndrome; Russell-Silver syndrome; and microcephalic osteodysplastic primordial dwarfism type 1 and 2. Russell-Silver syndrome is a rare genetic condition characterized by growth delays before birth, overgrowth of one side of the body, and unusual facial features. The range and severity of symptoms of Russell-Silver syndrome vary from person to person. The majority of those affected are of normal intelligence, but motor and/or speech delay is common. Growth delays before birth affect both weight and height. As such, affected infants may be small and have a low birth weight. In addition, growth delays and immature bone development continue after birth resulting in short stature. In most children, overgrowth of one side of the body is obvious at birth. This feature varies and may affect the head, trunk, arms, and/or legs. Facial features may include a triangular-shaped face with a small, pointed chin; a prominent forehead; bluish tint of the outer membranes covering the eyeballs; a small, wide mouth with downturned corners; and/or a small jaw. (For more information on this disorder, choose “Russell Silver syndrome” as your search term in the Rare Disease Database.) Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) is a genetic condition characterized by growth delays before and after birth, small head, skeletal abnormalities, distinctive facial features; and brain anomalies. Other signs and symptoms include sparse hair and eyebrows, dry skin, short limbs, dislocation of the hips and elbows, seizures; and intellectual disability.MOPD1 is caused by mutations in the RNU4ATAC gene and is inherited in an autosomal recessive manner. Microcephalic osteodysplastic primordial dwarfism type 2 (MOPD2) is an extremely rare genetic disorder. Features include short stature, a small head, and skeletal abnormalities. Other physical findings can be unusual skin color, blood vessel abnormalities, and/or a high-pitched voice. Severe growth deficiency before birth commonly occurs. Intellectual disability may be present in some children. Specific symptoms and severity vary from person to person. MOPD2 is caused by mutations in the PCNT gene and is inherited in an autosomal recessive fashion. Three M syndrome is an extremely rare genetic disorder with low birth weight, short stature, abnormalities of the head and face, distinctive skeletal defects, and/or other physical features. Intellectual ability is normal with this syndrome. Facial features typically include a long, narrow head, a prominent forehead, and a triangular-shaped face with a prominent, pointed chin, large ears, and/or abnormally flat cheeks. There are some patients reported to have abnormally crowded teeth. Skeletal abnormalities include very thin arm and leg bones; long, thin bones of the spinal column; and/or defects with the ribs and shoulder blades. Affected people may also have permanent fixation of certain fingers in a bent position, short fifth fingers, and/or highly flexible joints. The range and severity of symptoms and physical features may vary from person to person. Three M syndrome is inherited in an autosomal recessive pattern. (For more information on this disorder, choose “three M syndrome” as your search term in the Rare Disease Database.)
| 782 |
Meier-Gorlin Syndrome
|
nord_782_5
|
Diagnosis of Meier-Gorlin Syndrome
|
MGS is diagnosed based on the clinical signs and symptoms. The presence of small ears, very small or absent kneecaps and short stature are essential for the clinical diagnosis of MGS. MGS may be diagnosed at birth, based on detailed medical history, physical examination, and other tests, including imaging of the kneecaps. Further bone development may be diagnosed through careful view of the entire bone system using imaging options such as an x-ray. Genetic testing for changes in the ORC1, MCM5, GMNN, CDC45, ORC4, ORC6, CDT1, or CDC6 genes can confirm a suspected diagnosis. Gene changes have been detected in about 78% of patients with MGS. Clinical Testing and Work-Up
In infants with suspected MGS, ultrasound is advised to view the kneecaps. Kneecaps are not able to be seen on x-rays within the first 5-6 years of life. There are no official guidelines for diagnostic evaluation for MGS patients. However, it is recommended to have a hearing evaluation, a cardiac evaluation, knee imaging, and a developmental growth evaluation, with other evaluations as needed based on symptoms.
|
Diagnosis of Meier-Gorlin Syndrome. MGS is diagnosed based on the clinical signs and symptoms. The presence of small ears, very small or absent kneecaps and short stature are essential for the clinical diagnosis of MGS. MGS may be diagnosed at birth, based on detailed medical history, physical examination, and other tests, including imaging of the kneecaps. Further bone development may be diagnosed through careful view of the entire bone system using imaging options such as an x-ray. Genetic testing for changes in the ORC1, MCM5, GMNN, CDC45, ORC4, ORC6, CDT1, or CDC6 genes can confirm a suspected diagnosis. Gene changes have been detected in about 78% of patients with MGS. Clinical Testing and Work-Up
In infants with suspected MGS, ultrasound is advised to view the kneecaps. Kneecaps are not able to be seen on x-rays within the first 5-6 years of life. There are no official guidelines for diagnostic evaluation for MGS patients. However, it is recommended to have a hearing evaluation, a cardiac evaluation, knee imaging, and a developmental growth evaluation, with other evaluations as needed based on symptoms.
| 782 |
Meier-Gorlin Syndrome
|
nord_782_6
|
Therapies of Meier-Gorlin Syndrome
|
Treatment
The treatment of MGS is directed towards specific symptoms or complaints. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who assess and treat hearing problems (audiologists), those who specialize in diagnosing and treating skeletal defects (orthopedists), and other health care professionals may be involved. Pediatricians need to closely monitor an affected child's feeding, growth patterns, and breathing problems. This is important since poor weight gain and recurrent infections are the most serious problems associated with MGS during early infancy and childhood. Genetic counseling is recommended for affected individuals, their siblings and parents.
|
Therapies of Meier-Gorlin Syndrome. Treatment
The treatment of MGS is directed towards specific symptoms or complaints. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who assess and treat hearing problems (audiologists), those who specialize in diagnosing and treating skeletal defects (orthopedists), and other health care professionals may be involved. Pediatricians need to closely monitor an affected child's feeding, growth patterns, and breathing problems. This is important since poor weight gain and recurrent infections are the most serious problems associated with MGS during early infancy and childhood. Genetic counseling is recommended for affected individuals, their siblings and parents.
| 782 |
Meier-Gorlin Syndrome
|
nord_783_0
|
Overview of Meige Syndrome
|
Meige syndrome is a rare neurological movement disorder characterized by involuntary and often forceful contractions of the muscles of the jaw and tongue (oromandibular dystonia) and involuntary muscle spasms and contractions of the muscles around the eyes (blepharospasm). The specific symptoms and their severity vary from case to case.Meige syndrome belongs to a group of disorders known as dystonia. Dystonia is a group of movement disorders that vary in their symptoms, causes, progression, and treatments. This group of neurological conditions is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). The exact cause of Meige syndrome is unknown.
|
Overview of Meige Syndrome. Meige syndrome is a rare neurological movement disorder characterized by involuntary and often forceful contractions of the muscles of the jaw and tongue (oromandibular dystonia) and involuntary muscle spasms and contractions of the muscles around the eyes (blepharospasm). The specific symptoms and their severity vary from case to case.Meige syndrome belongs to a group of disorders known as dystonia. Dystonia is a group of movement disorders that vary in their symptoms, causes, progression, and treatments. This group of neurological conditions is generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). The exact cause of Meige syndrome is unknown.
| 783 |
Meige Syndrome
|
nord_783_1
|
Symptoms of Meige Syndrome
|
Meige syndrome is characterized by the combination of blepharospasm and oromandibular dystonia. The severity of these conditions varies from case to case. Meige syndrome most often affects middle-aged individuals. Blepharospasm is characterized by frequent or forced blinking and eye irritation that often occurs as a result of specific stimuli including bright lights, fatigue, emotional tension, and environmental factors such as wind or air pollution. The frequency of muscle spasms and contractions may increase causing narrowing of the opening between the eyelids or involuntary closure of the eyelids. It may become progressively harder for affected individuals to keep their eyes open. Blepharospasm may originally affect one eye (unilateral), but usually becomes (bilateral). Some individuals with Meige syndrome may experience abnormally dry eyes.Oromandibular dystonia is characterized by involuntary, forceful contractions of the jaw and tongue, often making it difficult to open or close the mouth. Some individuals may also experience clenching or grinding of the teeth, displacement of the jaw, grimacing, chin thrusting, or repeated pursing of the lips. Eyelid and facial muscle tone may gradually decline. Some people with Meige syndrome may also experience spasms of the tongue and throat, resulting in repeated protrusion of the tongue from the mouth and difficulty swallowing. Muscle spasms of the respiratory tract may lead to breathing difficulties (dyspnea). In some cases, muscles in the neck, arms, legs or other muscle groups may become affected.
|
Symptoms of Meige Syndrome. Meige syndrome is characterized by the combination of blepharospasm and oromandibular dystonia. The severity of these conditions varies from case to case. Meige syndrome most often affects middle-aged individuals. Blepharospasm is characterized by frequent or forced blinking and eye irritation that often occurs as a result of specific stimuli including bright lights, fatigue, emotional tension, and environmental factors such as wind or air pollution. The frequency of muscle spasms and contractions may increase causing narrowing of the opening between the eyelids or involuntary closure of the eyelids. It may become progressively harder for affected individuals to keep their eyes open. Blepharospasm may originally affect one eye (unilateral), but usually becomes (bilateral). Some individuals with Meige syndrome may experience abnormally dry eyes.Oromandibular dystonia is characterized by involuntary, forceful contractions of the jaw and tongue, often making it difficult to open or close the mouth. Some individuals may also experience clenching or grinding of the teeth, displacement of the jaw, grimacing, chin thrusting, or repeated pursing of the lips. Eyelid and facial muscle tone may gradually decline. Some people with Meige syndrome may also experience spasms of the tongue and throat, resulting in repeated protrusion of the tongue from the mouth and difficulty swallowing. Muscle spasms of the respiratory tract may lead to breathing difficulties (dyspnea). In some cases, muscles in the neck, arms, legs or other muscle groups may become affected.
| 783 |
Meige Syndrome
|
nord_783_2
|
Causes of Meige Syndrome
|
The cause of Meige syndrome is unknown. Researchers speculate that the cause of Meige syndrome may be multifactorial (e.g., caused by the interaction of certain genetic and environmental factors). Malfunctioning of a region of the brain known as the basal ganglia may play a role in the development of Meige syndrome. The basal ganglia is a structure composed of nerve cells located at the base of the brain. The basal ganglia is involved in the regulation of motor and learning functions. The exact problem(s) associated with the basal ganglia in individuals with Meige syndrome is unknown.Some cases of oromandibular dystonia occur in association with or secondary to another disorder such as tardive dyskinesia, Wilson disease, and Parkinson disease.
|
Causes of Meige Syndrome. The cause of Meige syndrome is unknown. Researchers speculate that the cause of Meige syndrome may be multifactorial (e.g., caused by the interaction of certain genetic and environmental factors). Malfunctioning of a region of the brain known as the basal ganglia may play a role in the development of Meige syndrome. The basal ganglia is a structure composed of nerve cells located at the base of the brain. The basal ganglia is involved in the regulation of motor and learning functions. The exact problem(s) associated with the basal ganglia in individuals with Meige syndrome is unknown.Some cases of oromandibular dystonia occur in association with or secondary to another disorder such as tardive dyskinesia, Wilson disease, and Parkinson disease.
| 783 |
Meige Syndrome
|
nord_783_3
|
Affects of Meige Syndrome
|
Meige syndrome affects women more often than men. Symptoms typically begin in middle-age between 40-70 years, although cases have been reported in individuals much younger. The disorder was first described in detail in the medical literature in 1910 by French neurologist Henry Meige.
|
Affects of Meige Syndrome. Meige syndrome affects women more often than men. Symptoms typically begin in middle-age between 40-70 years, although cases have been reported in individuals much younger. The disorder was first described in detail in the medical literature in 1910 by French neurologist Henry Meige.
| 783 |
Meige Syndrome
|
nord_783_4
|
Related disorders of Meige Syndrome
|
Symptoms of the following disorders can be similar to those of Meige syndrome. Comparisons may be useful for a differential diagnosis.Dystonia is a group of neurological movement disorders characterized by involuntary muscle contractions. Dystonia may be focal (affecting an isolated body part), segmental (affecting adjacent body areas, or generalized (affecting many major muscle groups simultaneously). Dystonia may result in abnormal, often painful movements or postures. There are many different causes for dystonia. Genetic as well as non-genetic factors contribute to all forms of dystonia. (For more information on this disorder, choose “dystonia” as your search term in the Rare Disease Database.) Temporomandibular joint (TMJ) dysfunction is a general term for a group of conditions that affect the temporomandibular joint. The TMJs are small joints that connect the lower jaw (mandible) to the temporal bone of the skull. TMJ dysfunction is characterized by pain of the jaw joint that is made worse during or after eating or yawning. It can cause limited jaw movement and clicks and pops during chewing. In severe cases, pain can radiate into the neck, shoulders and back. There are many suspected causes of TMJ dysfunction. The only definite cause is trauma to the jaw as from a heavy blow to the mouth. (For more information on this disorder, choose “temporomandibular joint dysfunction” as your search term in the Rare Disease Database.)Benign essential blepharospasm (BEB) is a rare neurological disorder in which affected individuals experience involuntary muscle spasms and contractions of the muscles around the eye. These spasms come and go (intermittent). Symptoms may begin as eye twitching, blinking and/or irritation. Eventually, BEB causes involuntary closure of the eyes. The exact cause of BEB is unknown. The disorder is one of a group of disorders collectively known as dystonia. (For more information on this disorder, choose “blepharospasm” as your search term in the Rare Disease Database.)Tardive dyskinesia (TD) is an involuntary neurological movement disorder caused by the use of neuroleptic drugs that are prescribed to treat certain psychiatric or gastrointestinal conditions. Long-term use of these drugs may produce biochemical abnormalities in the area of the brain known as the striatum. The reasons that some people who take these drugs may develop tardive dyskinesia, and some people do not, is unknown. tardive dystonia is believed to be the more severe form of tardive dyskinesia. (For more information on this disorder, choose “tardive dyskinesia” as your search term in the Rare Disease Database.)Hemifacial spasm, which is characterized by contractions on one side of the face, is technically not a form of dystonia. The initial symptom of hemifacial spasm may be twitching of the eyelids that eventually results in forced closure of the eyelid. Hemifacial spasm may be caused by inflammation of irritation to a facial nerve. (For more information on this disorder, choose “Hemifacial Spasm” as your search term in the Rare Disease Database.)
|
Related disorders of Meige Syndrome. Symptoms of the following disorders can be similar to those of Meige syndrome. Comparisons may be useful for a differential diagnosis.Dystonia is a group of neurological movement disorders characterized by involuntary muscle contractions. Dystonia may be focal (affecting an isolated body part), segmental (affecting adjacent body areas, or generalized (affecting many major muscle groups simultaneously). Dystonia may result in abnormal, often painful movements or postures. There are many different causes for dystonia. Genetic as well as non-genetic factors contribute to all forms of dystonia. (For more information on this disorder, choose “dystonia” as your search term in the Rare Disease Database.) Temporomandibular joint (TMJ) dysfunction is a general term for a group of conditions that affect the temporomandibular joint. The TMJs are small joints that connect the lower jaw (mandible) to the temporal bone of the skull. TMJ dysfunction is characterized by pain of the jaw joint that is made worse during or after eating or yawning. It can cause limited jaw movement and clicks and pops during chewing. In severe cases, pain can radiate into the neck, shoulders and back. There are many suspected causes of TMJ dysfunction. The only definite cause is trauma to the jaw as from a heavy blow to the mouth. (For more information on this disorder, choose “temporomandibular joint dysfunction” as your search term in the Rare Disease Database.)Benign essential blepharospasm (BEB) is a rare neurological disorder in which affected individuals experience involuntary muscle spasms and contractions of the muscles around the eye. These spasms come and go (intermittent). Symptoms may begin as eye twitching, blinking and/or irritation. Eventually, BEB causes involuntary closure of the eyes. The exact cause of BEB is unknown. The disorder is one of a group of disorders collectively known as dystonia. (For more information on this disorder, choose “blepharospasm” as your search term in the Rare Disease Database.)Tardive dyskinesia (TD) is an involuntary neurological movement disorder caused by the use of neuroleptic drugs that are prescribed to treat certain psychiatric or gastrointestinal conditions. Long-term use of these drugs may produce biochemical abnormalities in the area of the brain known as the striatum. The reasons that some people who take these drugs may develop tardive dyskinesia, and some people do not, is unknown. tardive dystonia is believed to be the more severe form of tardive dyskinesia. (For more information on this disorder, choose “tardive dyskinesia” as your search term in the Rare Disease Database.)Hemifacial spasm, which is characterized by contractions on one side of the face, is technically not a form of dystonia. The initial symptom of hemifacial spasm may be twitching of the eyelids that eventually results in forced closure of the eyelid. Hemifacial spasm may be caused by inflammation of irritation to a facial nerve. (For more information on this disorder, choose “Hemifacial Spasm” as your search term in the Rare Disease Database.)
| 783 |
Meige Syndrome
|
nord_783_5
|
Diagnosis of Meige Syndrome
|
No tests exist to diagnose Meige syndrome. A diagnosis is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic symptoms.
|
Diagnosis of Meige Syndrome. No tests exist to diagnose Meige syndrome. A diagnosis is made based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic symptoms.
| 783 |
Meige Syndrome
|
nord_783_6
|
Therapies of Meige Syndrome
|
TreatmentThe treatment of Meige syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment consists of drug therapy and botulinum A toxin (Botox) injections used separately or in combination.Approximately one-third of affected individuals are treated with oral medications (drug therapy). Unfortunately, the results of these drug treatments are usually moderate or unsatisfactory and often temporary. No drugs appear to be uniformly effective. Drugs that have been used to treat Meige syndrome include clonazepam, trihexyphenidyl, diazepam, and baclofen.The orphan drug botulinum A toxin (BOTOX) has been approved by the Food and Drug Administration (FDA) as a treatment for blepharospasm and has become the primary form of treatment. The technique of injecting small amounts of botulinum toxin into the orbicularis oculi paralyzes these muscles for several months, after which time the procedure must be repeated. Botulinum toxin injections have been helpful for many individuals with blepharospasm, but some people do not respond well. The drug is distributed by Allergan, Inc. For more information patients should ask their physician to contact: Allergan Inc., 2525 Dupont Drive, Irvine, CA 92713-9534.BOTOX is also used to treat muscle spasms associated with oromandibular dysontia. Approximately 70 percent of individuals experience some reduction of spasm and improvement in chewing and swallowing following injection with BOTOX.In some cases, individuals may experience relief of symptoms by engaging in specific movements sometimes referred to as "sensory tricks." Such movements include biting on a toothpick, chewing gums, talking, or lightly touching the lips or chin. Speech and swallowing therapy may lessen spasms, improve range of motion, and strengthened unaffected muscles.According to the medical literature, some individuals with blepharospasm and/or oromandibular dystonia have improved without treatment (spontaneous remission).
|
Therapies of Meige Syndrome. TreatmentThe treatment of Meige syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment consists of drug therapy and botulinum A toxin (Botox) injections used separately or in combination.Approximately one-third of affected individuals are treated with oral medications (drug therapy). Unfortunately, the results of these drug treatments are usually moderate or unsatisfactory and often temporary. No drugs appear to be uniformly effective. Drugs that have been used to treat Meige syndrome include clonazepam, trihexyphenidyl, diazepam, and baclofen.The orphan drug botulinum A toxin (BOTOX) has been approved by the Food and Drug Administration (FDA) as a treatment for blepharospasm and has become the primary form of treatment. The technique of injecting small amounts of botulinum toxin into the orbicularis oculi paralyzes these muscles for several months, after which time the procedure must be repeated. Botulinum toxin injections have been helpful for many individuals with blepharospasm, but some people do not respond well. The drug is distributed by Allergan, Inc. For more information patients should ask their physician to contact: Allergan Inc., 2525 Dupont Drive, Irvine, CA 92713-9534.BOTOX is also used to treat muscle spasms associated with oromandibular dysontia. Approximately 70 percent of individuals experience some reduction of spasm and improvement in chewing and swallowing following injection with BOTOX.In some cases, individuals may experience relief of symptoms by engaging in specific movements sometimes referred to as "sensory tricks." Such movements include biting on a toothpick, chewing gums, talking, or lightly touching the lips or chin. Speech and swallowing therapy may lessen spasms, improve range of motion, and strengthened unaffected muscles.According to the medical literature, some individuals with blepharospasm and/or oromandibular dystonia have improved without treatment (spontaneous remission).
| 783 |
Meige Syndrome
|
nord_784_0
|
Overview of Melanoma, Malignant
|
Malignant Melanoma is a common skin cancer that arises from the melanin cells within the upper layer of the skin (epidermis) or from similar cells that may be found in moles (nevi). This type of skin cancer may send down roots into deeper layers of the skin. Some of these microscopic roots may spread (metastasize) causing new tumor growths in vital organs of the body.
|
Overview of Melanoma, Malignant. Malignant Melanoma is a common skin cancer that arises from the melanin cells within the upper layer of the skin (epidermis) or from similar cells that may be found in moles (nevi). This type of skin cancer may send down roots into deeper layers of the skin. Some of these microscopic roots may spread (metastasize) causing new tumor growths in vital organs of the body.
| 784 |
Melanoma, Malignant
|
nord_784_1
|
Symptoms of Melanoma, Malignant
|
In the early stages, most melanomas do not produce any specific symptoms. Later they may appear as lesions that do not heal or an existing mole that shows changes in size or color. A physician should be consulted when any lesion, pigmented or not, becomes itchy, burns, softens or hardens, forms a scab, bleeds, becomes surrounded by a reddened or inflamed area, changes color, size, or shape.Disorder Subdivisions:Acral Lentiginious melanoma is a malignant skin cancer that occurs in areas that are not excessively exposed to sunlight and where hair follicles are absent.Juvenile Melanoma is a benign, elevated, pink to purplish-red papule, with a slightly scaly surface. It usually appears on the face, especially the cheeks. This type of melanoma most often occurs before puberty and may be mistaken for malignant melanoma.Malignant Lentigo (Melanoma) is a precancerous area on the skin that resembles a freckle. It may be brown or black in color and irregular in shape; it usually occurs on the face. This type of Melanoma occurs most often in older people.
|
Symptoms of Melanoma, Malignant. In the early stages, most melanomas do not produce any specific symptoms. Later they may appear as lesions that do not heal or an existing mole that shows changes in size or color. A physician should be consulted when any lesion, pigmented or not, becomes itchy, burns, softens or hardens, forms a scab, bleeds, becomes surrounded by a reddened or inflamed area, changes color, size, or shape.Disorder Subdivisions:Acral Lentiginious melanoma is a malignant skin cancer that occurs in areas that are not excessively exposed to sunlight and where hair follicles are absent.Juvenile Melanoma is a benign, elevated, pink to purplish-red papule, with a slightly scaly surface. It usually appears on the face, especially the cheeks. This type of melanoma most often occurs before puberty and may be mistaken for malignant melanoma.Malignant Lentigo (Melanoma) is a precancerous area on the skin that resembles a freckle. It may be brown or black in color and irregular in shape; it usually occurs on the face. This type of Melanoma occurs most often in older people.
| 784 |
Melanoma, Malignant
|
nord_784_2
|
Causes of Melanoma, Malignant
|
The exact cause of Malignant Melanoma is unknown. Excessive exposure to the sun, particularly before puberty, and living in areas that are closer to the sun (i.e., tropical climates), increases the risk of developing skin cancer. A defective gene known as CDK4 has been identified and may be associated with an increased risk for familial Malignant Melanoma. Approximately ten percent of people with Malignant Melanoma may have the familial form of the disease. This familial tendency may be transmitted through autosomal dominant genes. A genetic predisposition to an illness means that some people may carry the defective gene but never get the disorder unless something in the environment triggers the diseaseHuman traits including the classic genetic diseases are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
|
Causes of Melanoma, Malignant. The exact cause of Malignant Melanoma is unknown. Excessive exposure to the sun, particularly before puberty, and living in areas that are closer to the sun (i.e., tropical climates), increases the risk of developing skin cancer. A defective gene known as CDK4 has been identified and may be associated with an increased risk for familial Malignant Melanoma. Approximately ten percent of people with Malignant Melanoma may have the familial form of the disease. This familial tendency may be transmitted through autosomal dominant genes. A genetic predisposition to an illness means that some people may carry the defective gene but never get the disorder unless something in the environment triggers the diseaseHuman traits including the classic genetic diseases are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
| 784 |
Melanoma, Malignant
|
nord_784_3
|
Affects of Melanoma, Malignant
|
Malignant Melanoma affects males and females in equal numbers. The incidence of these types of skin cancers is increasing at a relatively fast rate as compared with other forms of cancer. The risk of melanoma is higher in people of European descent than in other populations. A darker pigmentation to the skin may be associated with a lower risk of Malignant Melanoma. It is also associated with a greater risk for those individuals with blue eyes and a fair complexion.In 1995, approximately 34,000 Americans were diagnosed with Malignant Melanoma; it is thought to affect approximately 40,300 Americans every year. In addition, each year in the US and Canada, between 1,680 and 2, 240 individuals are diagnosed with ocular melanoma.
|
Affects of Melanoma, Malignant. Malignant Melanoma affects males and females in equal numbers. The incidence of these types of skin cancers is increasing at a relatively fast rate as compared with other forms of cancer. The risk of melanoma is higher in people of European descent than in other populations. A darker pigmentation to the skin may be associated with a lower risk of Malignant Melanoma. It is also associated with a greater risk for those individuals with blue eyes and a fair complexion.In 1995, approximately 34,000 Americans were diagnosed with Malignant Melanoma; it is thought to affect approximately 40,300 Americans every year. In addition, each year in the US and Canada, between 1,680 and 2, 240 individuals are diagnosed with ocular melanoma.
| 784 |
Melanoma, Malignant
|
nord_784_4
|
Related disorders of Melanoma, Malignant
|
Symptoms of the following disorders can be similar to those of Malignant Melanoma. Comparisons may be useful for a differential diagnosis:Basal Cell Carcinoma is a common skin cancer. It may appear as small, shiny, firm nodules; ulcerated, crusted lesions; or flat, scar-like hardened patches that may bleed. Without a biopsy, this type of skin cancer is difficult to differentiate from psoriasis or localized dermatitis.Squamous Cell Carcinomas usually appear on sun-exposed areas of the skin, but may occur anywhere on the body. The lesions begin as small red elevations or patches with a scaly or crusted surface. They may become nodular, sometimes with a warty surface. In some patients, the bulk of the lesion may lie below the level of the surrounding tissue. A biopsy is essential to diagnose this disorder.Kaposi's Sarcoma (KS) may appear as small, tan-to-purple pigmented papules, plaques, nodules, tumors, or ulcers. This type of skin cancer may infiltrate the body, involving the oropharynx and gastrointestinal tract, disseminating to other organs such as the liver, lung, and bone. Chemotherapy has been helpful in treating Kaposi's Sarcoma. Up until the last decade, KS was reported mostly in older men of Ashkenazi Jewish or Mediterranean descent and those with a compromised immune system. The more recent increased incidence of Kaposi's Sarcoma is due to AIDS (Acquired Immunodeficiency Syndrome); about 30% of those with AIDS will also be diagnosed with Kaposi's Sarcoma.
|
Related disorders of Melanoma, Malignant. Symptoms of the following disorders can be similar to those of Malignant Melanoma. Comparisons may be useful for a differential diagnosis:Basal Cell Carcinoma is a common skin cancer. It may appear as small, shiny, firm nodules; ulcerated, crusted lesions; or flat, scar-like hardened patches that may bleed. Without a biopsy, this type of skin cancer is difficult to differentiate from psoriasis or localized dermatitis.Squamous Cell Carcinomas usually appear on sun-exposed areas of the skin, but may occur anywhere on the body. The lesions begin as small red elevations or patches with a scaly or crusted surface. They may become nodular, sometimes with a warty surface. In some patients, the bulk of the lesion may lie below the level of the surrounding tissue. A biopsy is essential to diagnose this disorder.Kaposi's Sarcoma (KS) may appear as small, tan-to-purple pigmented papules, plaques, nodules, tumors, or ulcers. This type of skin cancer may infiltrate the body, involving the oropharynx and gastrointestinal tract, disseminating to other organs such as the liver, lung, and bone. Chemotherapy has been helpful in treating Kaposi's Sarcoma. Up until the last decade, KS was reported mostly in older men of Ashkenazi Jewish or Mediterranean descent and those with a compromised immune system. The more recent increased incidence of Kaposi's Sarcoma is due to AIDS (Acquired Immunodeficiency Syndrome); about 30% of those with AIDS will also be diagnosed with Kaposi's Sarcoma.
| 784 |
Melanoma, Malignant
|
nord_784_5
|
Diagnosis of Melanoma, Malignant
|
Diagnosis of Melanoma, Malignant.
| 784 |
Melanoma, Malignant
|
|
nord_784_6
|
Therapies of Melanoma, Malignant
|
The treatment for malignant melanoma depends on the level, stage, and location of the skin cancer at the time of diagnosis. For stage 1 disease, surgery to remove the affected area involves a wide excision with 5 cm margins around the lesion. In some locations, such as the face, smaller margins must be accepted. In Stage 2 disease, the cancer has progressed to the lymph nodes; additional surgery then involves complete removal of the involved nodes (lymphadenectomy). Regular follow-ups are advisable and typically include an annual chest x-ray.For individuals with metastatic disease, certain chemotherapeutic agents (drugs) are being used alone or in combination with other drugs. Decarbazine, used in this manner has resulted in a temporary remission for some patients. A course of treatment that includes high-dose alkylating agents, such as cyclophosphamide, cisplatin, and carmustine, may also be effective as a treatment for malignant melanoma.The FDA has approved the use of the orphan drug Aldesleukin (Proleukin) for metastatic melanoma. The drug is made by:The Chiron Corporation4560 Horton StreetEmeryville, C. 94608The drug Intron A (alpha-interferon) has been recommended for approval for the treatment of people with malignant melanoma who have also had surgery (adjuvant therapy). Intron A is manufactured by Schering-Plough.Researchers from Yale University recently proposed new guidelines for follow-up of individuals with melanoma. Based upon the potential for recurrences, researchers recommend the following surveillance schedule for the detection of recurrences:Stage 1 – annually.Stage 2 – every six months for the first two years and annually thereafter.Stage 3 – every three months for the first year, every four months for the second year, every six months for years 3 to 5, and annually for year six and beyond.
|
Therapies of Melanoma, Malignant. The treatment for malignant melanoma depends on the level, stage, and location of the skin cancer at the time of diagnosis. For stage 1 disease, surgery to remove the affected area involves a wide excision with 5 cm margins around the lesion. In some locations, such as the face, smaller margins must be accepted. In Stage 2 disease, the cancer has progressed to the lymph nodes; additional surgery then involves complete removal of the involved nodes (lymphadenectomy). Regular follow-ups are advisable and typically include an annual chest x-ray.For individuals with metastatic disease, certain chemotherapeutic agents (drugs) are being used alone or in combination with other drugs. Decarbazine, used in this manner has resulted in a temporary remission for some patients. A course of treatment that includes high-dose alkylating agents, such as cyclophosphamide, cisplatin, and carmustine, may also be effective as a treatment for malignant melanoma.The FDA has approved the use of the orphan drug Aldesleukin (Proleukin) for metastatic melanoma. The drug is made by:The Chiron Corporation4560 Horton StreetEmeryville, C. 94608The drug Intron A (alpha-interferon) has been recommended for approval for the treatment of people with malignant melanoma who have also had surgery (adjuvant therapy). Intron A is manufactured by Schering-Plough.Researchers from Yale University recently proposed new guidelines for follow-up of individuals with melanoma. Based upon the potential for recurrences, researchers recommend the following surveillance schedule for the detection of recurrences:Stage 1 – annually.Stage 2 – every six months for the first two years and annually thereafter.Stage 3 – every three months for the first year, every four months for the second year, every six months for years 3 to 5, and annually for year six and beyond.
| 784 |
Melanoma, Malignant
|
nord_785_0
|
Overview of MELAS Syndrome
|
MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) syndrome is a rare disorder that begins in childhood, usually between two and fifteen years of age, and mostly affects the nervous system and muscles. The most common early symptoms are seizures, recurrent headaches, loss of appetite and recurrent vomiting. Stroke-like episodes with temporary muscle weakness on one side of the body (hemiparesis) may also occur and this can lead to altered consciousness, vision and hearing loss, loss of motor skills and intellectual disability. MELAS is caused by mutations in mitochondrial DNA and in one patient, this syndrome has been associated with mutations in a nuclear gene, POLG1.
|
Overview of MELAS Syndrome. MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) syndrome is a rare disorder that begins in childhood, usually between two and fifteen years of age, and mostly affects the nervous system and muscles. The most common early symptoms are seizures, recurrent headaches, loss of appetite and recurrent vomiting. Stroke-like episodes with temporary muscle weakness on one side of the body (hemiparesis) may also occur and this can lead to altered consciousness, vision and hearing loss, loss of motor skills and intellectual disability. MELAS is caused by mutations in mitochondrial DNA and in one patient, this syndrome has been associated with mutations in a nuclear gene, POLG1.
| 785 |
MELAS Syndrome
|
nord_785_1
|
Symptoms of MELAS Syndrome
|
Symptoms of MELAS syndrome usually begin between the ages of two and fifteen years, but delayed onset cases have also been reported between fifteen and forty years and late onset cases after forty years. In approximately 75 percent of cases, onset of the disorder is before the age of 20 years. Symptoms and physical findings associated with MELAS syndrome vary greatly between affected individuals in the same family and between different families. The distinguishing feature in MELAS syndrome is the recurrence of stroke-like episodes. It is currently thought that the deficiency of a compound called nitric oxide in the small blood vessels of the brain may be responsible for the stroke-like episodes. Short stature and hearing loss may be present and fatigue and difficulty tolerating exercise may be early symptoms. People with MELAS syndrome have an accumulation of lactic acid in the blood (lactic acidosis), that can lead to vomiting, abdominal pain, fatigue, muscle weakness and difficulty breathing. This accumulation of lactic acid has also been noted in the spinal fluid and in the brain. In some cases, affected individuals will experience a slow deterioration of intellectual function (dementia), and/or a diminished ability to communicate by speech, writing, and/or signs (aphasia). Individuals with MELAS syndrome may also have episodes of confusion and hallucinations often due to a preceding fever (febrile illness) and/or headache. Less common symptoms include involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia), cardiomyopathy, diabetes mellitus, depression, bipolar disorder, gastrointestinal problems and kidney problems.
|
Symptoms of MELAS Syndrome. Symptoms of MELAS syndrome usually begin between the ages of two and fifteen years, but delayed onset cases have also been reported between fifteen and forty years and late onset cases after forty years. In approximately 75 percent of cases, onset of the disorder is before the age of 20 years. Symptoms and physical findings associated with MELAS syndrome vary greatly between affected individuals in the same family and between different families. The distinguishing feature in MELAS syndrome is the recurrence of stroke-like episodes. It is currently thought that the deficiency of a compound called nitric oxide in the small blood vessels of the brain may be responsible for the stroke-like episodes. Short stature and hearing loss may be present and fatigue and difficulty tolerating exercise may be early symptoms. People with MELAS syndrome have an accumulation of lactic acid in the blood (lactic acidosis), that can lead to vomiting, abdominal pain, fatigue, muscle weakness and difficulty breathing. This accumulation of lactic acid has also been noted in the spinal fluid and in the brain. In some cases, affected individuals will experience a slow deterioration of intellectual function (dementia), and/or a diminished ability to communicate by speech, writing, and/or signs (aphasia). Individuals with MELAS syndrome may also have episodes of confusion and hallucinations often due to a preceding fever (febrile illness) and/or headache. Less common symptoms include involuntary muscle spasms (myoclonus), impaired muscle coordination (ataxia), cardiomyopathy, diabetes mellitus, depression, bipolar disorder, gastrointestinal problems and kidney problems.
| 785 |
MELAS Syndrome
|
nord_785_2
|
Causes of MELAS Syndrome
|
MELAS is caused by mutations in mitochondrial DNA (mtDNA). Mutations affecting the genes for mtDNA are inherited from the mother. MtDNA that is found in sperm cells is typically lost during fertilization and as a result, all human mtDNA comes from the mother. An affected mother will pass on the mutation to all her children, but only her daughters will pass on the mutation to their children. Mitochondria, which are found by the hundreds or thousands in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production. Both normal and mutated mtDNA can exist in the same cell, a situation known as heteroplasmy. The number of defective mitochondria may be out-numbered by the number of normal mitochondria. Symptoms may not appear in any given generation until the mutation affects a significant proportion of mtDNA. The uneven distribution of normal and mutant mtDNA in different tissues can affect different organs in members of the same family. This can result in a variety of symptoms in affected family members.Mutations in the mtDNA gene MT-TL1 are associated with MELAS in approximately 80% of cases. Mutations in MT-TQ, MT-TH, MT-TK, MT-TS1, MT-ND1, MT-ND5, MT-ND6, and MT-TS2 have also been associated with MELAS syndrome.Some cases of MELAS syndrome appear to occur as the result of a new spontaneous mutation in a mitochondrial gene and are not inherited.In addition, mutations in a nuclear gene (POLG1) have been associated with MELAS syndrome in one case.
|
Causes of MELAS Syndrome. MELAS is caused by mutations in mitochondrial DNA (mtDNA). Mutations affecting the genes for mtDNA are inherited from the mother. MtDNA that is found in sperm cells is typically lost during fertilization and as a result, all human mtDNA comes from the mother. An affected mother will pass on the mutation to all her children, but only her daughters will pass on the mutation to their children. Mitochondria, which are found by the hundreds or thousands in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production. Both normal and mutated mtDNA can exist in the same cell, a situation known as heteroplasmy. The number of defective mitochondria may be out-numbered by the number of normal mitochondria. Symptoms may not appear in any given generation until the mutation affects a significant proportion of mtDNA. The uneven distribution of normal and mutant mtDNA in different tissues can affect different organs in members of the same family. This can result in a variety of symptoms in affected family members.Mutations in the mtDNA gene MT-TL1 are associated with MELAS in approximately 80% of cases. Mutations in MT-TQ, MT-TH, MT-TK, MT-TS1, MT-ND1, MT-ND5, MT-ND6, and MT-TS2 have also been associated with MELAS syndrome.Some cases of MELAS syndrome appear to occur as the result of a new spontaneous mutation in a mitochondrial gene and are not inherited.In addition, mutations in a nuclear gene (POLG1) have been associated with MELAS syndrome in one case.
| 785 |
MELAS Syndrome
|
nord_785_3
|
Affects of MELAS Syndrome
|
MELAS syndrome is a rare disorder that affects males and females in equal numbers. Although rare, MELAS syndrome is probably the most common type of mitochondrial myopathy caused by mutations in mtDNA. Some researchers believe that mitochondrial myopathies may go unrecognized and underdiagnosed in the general population, making it difficult to determine the true frequency of disorders like MELAS syndrome.
|
Affects of MELAS Syndrome. MELAS syndrome is a rare disorder that affects males and females in equal numbers. Although rare, MELAS syndrome is probably the most common type of mitochondrial myopathy caused by mutations in mtDNA. Some researchers believe that mitochondrial myopathies may go unrecognized and underdiagnosed in the general population, making it difficult to determine the true frequency of disorders like MELAS syndrome.
| 785 |
MELAS Syndrome
|
nord_785_4
|
Related disorders of MELAS Syndrome
|
Kearns-Sayre syndrome is a rare neuromuscular disorder characterized by three primary findings: progressive paralysis of certain eye muscles (chronic progressive external ophthalmoplegia); abnormal accumulation of colored (pigmented) material on the nerve-rich membrane lining the eyes (atypical retinitis pigmentosa), leading to chronic inflammation, progressive degeneration, and wearing away of certain eye structures (pigmentary degeneration of the retina); and heart disease such as heart block. Other findings may include muscle weakness, short stature, hearing loss, and/or the loss of ability to coordinate voluntary movements (ataxia) due to problems affecting part of the brain (cerebellum). In some cases, Kearns-Sayre syndrome may be associated with other disorders and/or conditions. (For more information on this disorder, choose “Kearns Sayre” as your search term in the Rare Disease Database.)MERRF syndrome (Myoclonus Epilepsy associated with Ragged-Red Fibers) is an extremely rare disorder that begins in childhood and affects the nervous system and muscles as well as other body systems. The distinguishing feature in MERRF syndrome is sudden, brief, jerking spasms that can affect the arms and legs or the entire body (myoclonic seizures). In addition, individuals with MERRF syndrome may have muscle weakness (myopathy), an impaired ability to coordinate movements (ataxia), seizures, and a slow deterioration of intellectual function (dementia). Short stature, degeneration of the optic nerve (optic atrophy), hearing loss and cardiomyopathy are also common symptoms. Abnormal muscle cells are present and appear as ragged red fibers when stained and viewed microscopically. MERRF is caused by mutations in mitochondrial DNA. (For more information on this disorder, choose “MERRF” as your search term in the Rare Disease Database.)Leigh disease is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh disease usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh disease progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. There appear to be several different types of genetically determined enzyme defects that can cause Leigh disease. Most individuals with Leigh disease have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most cases, Leigh disease is inherited as an autosomal recessive trait. However, X-linked recessive and mitochondrial inheritance have also been noted. (For more information on this disorder, choose “Leigh” as your search term in the Rare Disease Database.)
|
Related disorders of MELAS Syndrome. Kearns-Sayre syndrome is a rare neuromuscular disorder characterized by three primary findings: progressive paralysis of certain eye muscles (chronic progressive external ophthalmoplegia); abnormal accumulation of colored (pigmented) material on the nerve-rich membrane lining the eyes (atypical retinitis pigmentosa), leading to chronic inflammation, progressive degeneration, and wearing away of certain eye structures (pigmentary degeneration of the retina); and heart disease such as heart block. Other findings may include muscle weakness, short stature, hearing loss, and/or the loss of ability to coordinate voluntary movements (ataxia) due to problems affecting part of the brain (cerebellum). In some cases, Kearns-Sayre syndrome may be associated with other disorders and/or conditions. (For more information on this disorder, choose “Kearns Sayre” as your search term in the Rare Disease Database.)MERRF syndrome (Myoclonus Epilepsy associated with Ragged-Red Fibers) is an extremely rare disorder that begins in childhood and affects the nervous system and muscles as well as other body systems. The distinguishing feature in MERRF syndrome is sudden, brief, jerking spasms that can affect the arms and legs or the entire body (myoclonic seizures). In addition, individuals with MERRF syndrome may have muscle weakness (myopathy), an impaired ability to coordinate movements (ataxia), seizures, and a slow deterioration of intellectual function (dementia). Short stature, degeneration of the optic nerve (optic atrophy), hearing loss and cardiomyopathy are also common symptoms. Abnormal muscle cells are present and appear as ragged red fibers when stained and viewed microscopically. MERRF is caused by mutations in mitochondrial DNA. (For more information on this disorder, choose “MERRF” as your search term in the Rare Disease Database.)Leigh disease is a rare genetic neurometabolic disorder. It is characterized by the degeneration of the central nervous system (i.e., brain, spinal cord, and optic nerve). The symptoms of Leigh disease usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh disease progresses, symptoms may also include generalized weakness, lack of muscle tone (hypotonia), and episodes of lactic acidosis, which may lead to impairment of respiratory and kidney function. There appear to be several different types of genetically determined enzyme defects that can cause Leigh disease. Most individuals with Leigh disease have defects of mitochondrial energy production, such as deficiency of an enzyme of the mitochondrial respiratory chain complex or the pyruvate dehydrogenase complex. In most cases, Leigh disease is inherited as an autosomal recessive trait. However, X-linked recessive and mitochondrial inheritance have also been noted. (For more information on this disorder, choose “Leigh” as your search term in the Rare Disease Database.)
| 785 |
MELAS Syndrome
|
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.