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nord_714_2
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Causes of Leri Pleonosteosis
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When it was first identified, researchers believed that the signs of the disorder were due to the premature hardening (pleonosteosis) of the end portions of the long bones (epiphyses). However, since that time, some researchers have speculated that the basic abnormality may be the pulling away of specialized connective tissue (periosteal traction) from the shafts of the long bones (metaphyses).Leri pleonosteosis is inherited as an autosomal dominant genetic trait. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
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Causes of Leri Pleonosteosis. When it was first identified, researchers believed that the signs of the disorder were due to the premature hardening (pleonosteosis) of the end portions of the long bones (epiphyses). However, since that time, some researchers have speculated that the basic abnormality may be the pulling away of specialized connective tissue (periosteal traction) from the shafts of the long bones (metaphyses).Leri pleonosteosis is inherited as an autosomal dominant genetic trait. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
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Leri Pleonosteosis
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nord_714_3
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Affects of Leri Pleonosteosis
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Leri pleonosteosis is an extremely rare inherited disorder that affects males and females in equal numbers. Approximately 20 cases have been reported worldwide, with most of these outside of North America. The symptoms and physical characteristics associated with Leri pleonosteosis usually become apparent during infancy or early childhood.
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Affects of Leri Pleonosteosis. Leri pleonosteosis is an extremely rare inherited disorder that affects males and females in equal numbers. Approximately 20 cases have been reported worldwide, with most of these outside of North America. The symptoms and physical characteristics associated with Leri pleonosteosis usually become apparent during infancy or early childhood.
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Leri Pleonosteosis
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nord_714_4
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Related disorders of Leri Pleonosteosis
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Symptoms of the following disorders can be similar to those of Leri Pleonosteosis . Comparisons may be useful for a differential diagnosis:Acromicric Dysplasia is an extremely rare inherited disorder characterized by unusual facial features, abnormally short hands and feet, and/or severe growth retardation. Characteristic facial features may include abnormally narrow eyelid folds (palpebral fissures) and/or a short nose with nostrils that flare forward (anteverted nares). Malformation of the bones of the hands and feet (e.g., metacarpals and phalanges) may also be present. Acromicric Dysplasia is believed to result from a spontaneous genetic change that occurs for no unknown reasons (sporadic). In addition, some researchers believe that the disorder may be inherited as an autosomal dominant genetic trait.The following conditions may be associated with Leri Pleonosteosis as secondary characteristics. They are not necessary for a differential diagnosis:Carpal Tunnel Syndrome is a condition affecting the wrists and hands that results from compression of certain peripheral nerves (i.e., carpal nerve). It is characterized by a sensation of numbness, tingling, burning, and/or pain in the hands and/or wrists. Persons affected by this condition may be awakened at night with the feeling that their hands have “gone to sleep.” Carpal Tunnel Syndrome can appear in association with various other diseases or may occur as a single primary condition. (For more information on Carpal Tunnel Syndrome, choose “Carpal Tunnel” as your search term in the Rare Disease Database.)Morton Metatarsalgia, also known as Morton's Neuralgia, is a condition affecting the feet that results from compression of the plantar nerve. Persons affected by this condition may experience pain in their feet, especially of the 3rd and/or 4th toes. In some cases, affected individuals may experience a tingling or burning sensation. In some cases, chronic compression of the nerve may lead to the development of a tumor consisting of nerve cells and fibers (neuroma). Most cases of Morton Metatarsalgia occur as a result of trauma or injury to the nerves.
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Related disorders of Leri Pleonosteosis. Symptoms of the following disorders can be similar to those of Leri Pleonosteosis . Comparisons may be useful for a differential diagnosis:Acromicric Dysplasia is an extremely rare inherited disorder characterized by unusual facial features, abnormally short hands and feet, and/or severe growth retardation. Characteristic facial features may include abnormally narrow eyelid folds (palpebral fissures) and/or a short nose with nostrils that flare forward (anteverted nares). Malformation of the bones of the hands and feet (e.g., metacarpals and phalanges) may also be present. Acromicric Dysplasia is believed to result from a spontaneous genetic change that occurs for no unknown reasons (sporadic). In addition, some researchers believe that the disorder may be inherited as an autosomal dominant genetic trait.The following conditions may be associated with Leri Pleonosteosis as secondary characteristics. They are not necessary for a differential diagnosis:Carpal Tunnel Syndrome is a condition affecting the wrists and hands that results from compression of certain peripheral nerves (i.e., carpal nerve). It is characterized by a sensation of numbness, tingling, burning, and/or pain in the hands and/or wrists. Persons affected by this condition may be awakened at night with the feeling that their hands have “gone to sleep.” Carpal Tunnel Syndrome can appear in association with various other diseases or may occur as a single primary condition. (For more information on Carpal Tunnel Syndrome, choose “Carpal Tunnel” as your search term in the Rare Disease Database.)Morton Metatarsalgia, also known as Morton's Neuralgia, is a condition affecting the feet that results from compression of the plantar nerve. Persons affected by this condition may experience pain in their feet, especially of the 3rd and/or 4th toes. In some cases, affected individuals may experience a tingling or burning sensation. In some cases, chronic compression of the nerve may lead to the development of a tumor consisting of nerve cells and fibers (neuroma). Most cases of Morton Metatarsalgia occur as a result of trauma or injury to the nerves.
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Leri Pleonosteosis
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nord_714_5
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Diagnosis of Leri Pleonosteosis
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The diagnosis of Leri pleonosteosis may be established by a thorough clinical evaluation, characteristic physical findings, detailed patient history, and/or specialized tests including advanced imaging techniques (e.g., various x-ray methods). For example, enlargement of the cartilage that surrounds the upper spinal cord (posterior neural arches of the cervical vertebrae), is an important characteristic of this disorder and is potentially detectable by x-ray studies.
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Diagnosis of Leri Pleonosteosis. The diagnosis of Leri pleonosteosis may be established by a thorough clinical evaluation, characteristic physical findings, detailed patient history, and/or specialized tests including advanced imaging techniques (e.g., various x-ray methods). For example, enlargement of the cartilage that surrounds the upper spinal cord (posterior neural arches of the cervical vertebrae), is an important characteristic of this disorder and is potentially detectable by x-ray studies.
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Leri Pleonosteosis
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nord_714_6
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Therapies of Leri Pleonosteosis
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TreatmentThe treatment of Leri pleonosteosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal abnormalities (orthopedic specialists), and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.Children with Leri pleonosteosis should be observed for possible spinal cord compression that is sometimes associated with this disorder. Physical therapy may be recommended to help improve an affected individual's ability to walk and perform other movements independently (mobility). Other treatment is symptomatic and supportive.Genetic counseling will be of benefit for affected individuals and their families. A team approach for infants and children with this disorder may be of benefit and may include special social, educational, and medical services.
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Therapies of Leri Pleonosteosis. TreatmentThe treatment of Leri pleonosteosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who diagnose and treat skeletal abnormalities (orthopedic specialists), and other healthcare professionals may need to systematically and comprehensively plan an affected child's treatment.Children with Leri pleonosteosis should be observed for possible spinal cord compression that is sometimes associated with this disorder. Physical therapy may be recommended to help improve an affected individual's ability to walk and perform other movements independently (mobility). Other treatment is symptomatic and supportive.Genetic counseling will be of benefit for affected individuals and their families. A team approach for infants and children with this disorder may be of benefit and may include special social, educational, and medical services.
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Leri Pleonosteosis
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nord_715_0
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Overview of Leri-Weill Dyschondrosteosis
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Summary Leri-Weill dyschondrosteosis (LWD) is a rare genetic disorder characterized by abnormal shortening of the forearms and lower legs, abnormal misalignment of the wrist (Madelung deformity of the wrist), and associated short stature, which is defined as a child who has a height below percentile 3 (P3) for age, gender and population. Additional symptoms can also occur. The specific symptoms that develop and their severity can vary greatly from one person to another, even among members of the same family. Intelligence is unaffected. LWD is caused by a change (mutation) in the SHOX gene or its regulatory elements (enhancers) located on the pseudoautosomal region 1 (PAR1) of the sex chromosomes (further details described later). It is inherited as a “pseudoautosomal” trait.Introduction Leri-Weill dyschondrosteosis was first described in the medical literature in 1929 by doctors Léri and Weill. The disorder is a skeletal dysplasia and is associated with heterozygous mutations in the short stature homeobox-containing (SHOX) gene or its enhancers. Heterozygous means that an individual carries a single defective gene (i.e. a mutation in one SHOX gene, but not both). Additional disorders in the spectrum include the more severe skeletal dysplasia, Langer mesomelic dysplasia, which arises when there are two SHOX mutations, one on each chromosome (homozygous or compound heterozygous mutations), and in a small proportion (approximately 2.5%) of individuals with idiopathic short stature in which individuals only present with short stature.
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Overview of Leri-Weill Dyschondrosteosis. Summary Leri-Weill dyschondrosteosis (LWD) is a rare genetic disorder characterized by abnormal shortening of the forearms and lower legs, abnormal misalignment of the wrist (Madelung deformity of the wrist), and associated short stature, which is defined as a child who has a height below percentile 3 (P3) for age, gender and population. Additional symptoms can also occur. The specific symptoms that develop and their severity can vary greatly from one person to another, even among members of the same family. Intelligence is unaffected. LWD is caused by a change (mutation) in the SHOX gene or its regulatory elements (enhancers) located on the pseudoautosomal region 1 (PAR1) of the sex chromosomes (further details described later). It is inherited as a “pseudoautosomal” trait.Introduction Leri-Weill dyschondrosteosis was first described in the medical literature in 1929 by doctors Léri and Weill. The disorder is a skeletal dysplasia and is associated with heterozygous mutations in the short stature homeobox-containing (SHOX) gene or its enhancers. Heterozygous means that an individual carries a single defective gene (i.e. a mutation in one SHOX gene, but not both). Additional disorders in the spectrum include the more severe skeletal dysplasia, Langer mesomelic dysplasia, which arises when there are two SHOX mutations, one on each chromosome (homozygous or compound heterozygous mutations), and in a small proportion (approximately 2.5%) of individuals with idiopathic short stature in which individuals only present with short stature.
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Leri-Weill Dyschondrosteosis
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Symptoms of Leri-Weill Dyschondrosteosis
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The specific signs and symptoms associated with LWD can vary greatly from one person to another. Generally, females appear to be affected more severely than males. The classic findings of the disorder are mesomelic shortening of the limbs, short stature, and Madelung deformity. Some individuals do not develop Madelung deformity and/or may obtain normal height.Mesomelic shortening of the limbs describes abnormal shortening of the middle portion of the arms and legs in relation to the upper (proximal) portions, which means that the forearms and lower legs are disproportionately shorter than the upper arms and legs. Consequently, the arms and legs are disproportionate to the trunk of the body. Sometimes, the shin bone (tibia) and the lower arm (radius and ulna) may be abnormally bowed. Less often, wrist, knee or ankle pain may occur. Mesomelia usually first becomes apparent in school-aged children and can increase in frequency and severity with age. In LWD, the degree of short stature can vary greatly from one person to another. Often, short stature is mild and final adult height is only slightly reduced. Affected individuals may also have an abnormality of the wrist known as Madelung deformity that becomes more apparent around puberty. Madelung deformity is characterized by the bowing and shortening of the bones in the forearms (the radius and the ulna) and the dislocation of the ulna, resulting in the abnormal deviation or misalignment of the wrist. Generally, bilateral Madelung deformity is observed, i.e. both wrists are affected. Affected individuals may have a limited range of movements of the wrists and elbows and/or may experience wrist pain and visible changes in the appearance of the wrist.Additional symptoms may include a highly arched roof of the mouth (palate), short, thick middle bones of the hand (metacarpals), abnormal sideways curvature of the spine (scoliosis), and overgrowth (hypertrophy) of the calf muscles.
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Symptoms of Leri-Weill Dyschondrosteosis. The specific signs and symptoms associated with LWD can vary greatly from one person to another. Generally, females appear to be affected more severely than males. The classic findings of the disorder are mesomelic shortening of the limbs, short stature, and Madelung deformity. Some individuals do not develop Madelung deformity and/or may obtain normal height.Mesomelic shortening of the limbs describes abnormal shortening of the middle portion of the arms and legs in relation to the upper (proximal) portions, which means that the forearms and lower legs are disproportionately shorter than the upper arms and legs. Consequently, the arms and legs are disproportionate to the trunk of the body. Sometimes, the shin bone (tibia) and the lower arm (radius and ulna) may be abnormally bowed. Less often, wrist, knee or ankle pain may occur. Mesomelia usually first becomes apparent in school-aged children and can increase in frequency and severity with age. In LWD, the degree of short stature can vary greatly from one person to another. Often, short stature is mild and final adult height is only slightly reduced. Affected individuals may also have an abnormality of the wrist known as Madelung deformity that becomes more apparent around puberty. Madelung deformity is characterized by the bowing and shortening of the bones in the forearms (the radius and the ulna) and the dislocation of the ulna, resulting in the abnormal deviation or misalignment of the wrist. Generally, bilateral Madelung deformity is observed, i.e. both wrists are affected. Affected individuals may have a limited range of movements of the wrists and elbows and/or may experience wrist pain and visible changes in the appearance of the wrist.Additional symptoms may include a highly arched roof of the mouth (palate), short, thick middle bones of the hand (metacarpals), abnormal sideways curvature of the spine (scoliosis), and overgrowth (hypertrophy) of the calf muscles.
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nord_715_2
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Causes of Leri-Weill Dyschondrosteosis
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In most instances, LWD is caused by alterations (mutations) in or loss (deletion) of the short stature homeobox-containing (SHOX) gene or its regulatory regions. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The gene alterations that cause LWD are inherited in an autosomal or pseudoautosomal dominant manner. Pseudoautosomal inheritance is an extremely rare occurrence that involves a gene located both sex chromosomes, the X or Y chromosome. Genes are found on chromosomes, which are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair that normally consists of an X and Y chromosome for males and two X chromosomes for females. Chromosomes 1 through 22 are known as autosomes; the X and Y chromosomes are known as sex chromosomes.A gene on an autosome may be passed on to either a male or female child with equal likelihood. This is referred to as autosomal inheritance. However, the sex chromosomes (X and Y) are not passed on equally because a father transmits his X chromosome to his daughters and his Y chromosome to his sons. This is referred to as sex-linked inheritance. A key aspect of sex-linked inheritance is the lack of matched gene pairs between X and Y chromosomes. However, very small areas of the X and Y chromosome have matched genes. During the normal division of reproductive (sex) cells (meiosis), these areas pair up and “crossover”. The genes located in these areas transmit in a fashion similar to genes found on autosomes (pseudoautosomal inheritance). SHOX is one of those genes which is found on the tip of both the X and Y chromosomes.
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Causes of Leri-Weill Dyschondrosteosis. In most instances, LWD is caused by alterations (mutations) in or loss (deletion) of the short stature homeobox-containing (SHOX) gene or its regulatory regions. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.The gene alterations that cause LWD are inherited in an autosomal or pseudoautosomal dominant manner. Pseudoautosomal inheritance is an extremely rare occurrence that involves a gene located both sex chromosomes, the X or Y chromosome. Genes are found on chromosomes, which are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair that normally consists of an X and Y chromosome for males and two X chromosomes for females. Chromosomes 1 through 22 are known as autosomes; the X and Y chromosomes are known as sex chromosomes.A gene on an autosome may be passed on to either a male or female child with equal likelihood. This is referred to as autosomal inheritance. However, the sex chromosomes (X and Y) are not passed on equally because a father transmits his X chromosome to his daughters and his Y chromosome to his sons. This is referred to as sex-linked inheritance. A key aspect of sex-linked inheritance is the lack of matched gene pairs between X and Y chromosomes. However, very small areas of the X and Y chromosome have matched genes. During the normal division of reproductive (sex) cells (meiosis), these areas pair up and “crossover”. The genes located in these areas transmit in a fashion similar to genes found on autosomes (pseudoautosomal inheritance). SHOX is one of those genes which is found on the tip of both the X and Y chromosomes.
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Leri-Weill Dyschondrosteosis
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nord_715_3
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Affects of Leri-Weill Dyschondrosteosis
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LWD is a rare disorder that can affect males or females. More cases of the disorder have been reported in the medical literature in females than in males by a 4:1 ratio. The prevalence is unknown, but often given as between 1 in 1000-2000 in the general population. However, many affected individuals may go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of LWD in the general population.
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Affects of Leri-Weill Dyschondrosteosis. LWD is a rare disorder that can affect males or females. More cases of the disorder have been reported in the medical literature in females than in males by a 4:1 ratio. The prevalence is unknown, but often given as between 1 in 1000-2000 in the general population. However, many affected individuals may go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of LWD in the general population.
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Leri-Weill Dyschondrosteosis
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nord_715_4
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Related disorders of Leri-Weill Dyschondrosteosis
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Differential diagnoses should include the other SHOX-related haploinsufficiency disorders and related conditions such as Turner syndrome and distal monosomy Xp. Langer mesomelic dysplasia is a very rare form of dwarfism that affects males and females equally and is inherited through an autosomal or pseudoautosomal recessive trait. SHOX mutations on both sex chromosomes, i.e. 2 mutations, cause this skeletal dysplasia. People with this disorder typically are very short (adult size 125cm) due to short, thick, curved bones of the radius (bone on the thumb side of the forearm) and tibia (larger of the two leg bones between the knee and ankle). Failure of growth or underdevelopment and bowing of the ulna (bone on the little finger side of the forearm) and fibula (smaller of the two bones in the leg between the knee and ankle) is also present. Other features of this disorder may be: restricted elbow and forearm movement, an underdeveloped lower jaw (micrognathia), and an abnormal degree of forward curvature of the lower back.Madelung deformity of the wrist can also occur by trauma or infection. In these cases, it is often not bilateral, i.e. does not affect both wrists. It is not inherited in such cases and is not associated with short stature. Madelung deformity can also occur as part of Turner syndrome (10% of cases), a rare chromosomal disorder that affects females.
Turner syndrome is caused by a loss (deletion) of genetic material on the X chromosome that can include SHOX. (For more information, choose “Turner syndrome” as your search term in the Rare Disease Database.)The clinical features of heterozygous NPR2 gene mutations which encode for the natriuretic peptide receptor B) in the CNP signaling pathway is similar to that of patients with LWD, with short forearms and lower legs (mesomelia) but none of the cases reported to date had Madelung deformity.
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Related disorders of Leri-Weill Dyschondrosteosis. Differential diagnoses should include the other SHOX-related haploinsufficiency disorders and related conditions such as Turner syndrome and distal monosomy Xp. Langer mesomelic dysplasia is a very rare form of dwarfism that affects males and females equally and is inherited through an autosomal or pseudoautosomal recessive trait. SHOX mutations on both sex chromosomes, i.e. 2 mutations, cause this skeletal dysplasia. People with this disorder typically are very short (adult size 125cm) due to short, thick, curved bones of the radius (bone on the thumb side of the forearm) and tibia (larger of the two leg bones between the knee and ankle). Failure of growth or underdevelopment and bowing of the ulna (bone on the little finger side of the forearm) and fibula (smaller of the two bones in the leg between the knee and ankle) is also present. Other features of this disorder may be: restricted elbow and forearm movement, an underdeveloped lower jaw (micrognathia), and an abnormal degree of forward curvature of the lower back.Madelung deformity of the wrist can also occur by trauma or infection. In these cases, it is often not bilateral, i.e. does not affect both wrists. It is not inherited in such cases and is not associated with short stature. Madelung deformity can also occur as part of Turner syndrome (10% of cases), a rare chromosomal disorder that affects females.
Turner syndrome is caused by a loss (deletion) of genetic material on the X chromosome that can include SHOX. (For more information, choose “Turner syndrome” as your search term in the Rare Disease Database.)The clinical features of heterozygous NPR2 gene mutations which encode for the natriuretic peptide receptor B) in the CNP signaling pathway is similar to that of patients with LWD, with short forearms and lower legs (mesomelia) but none of the cases reported to date had Madelung deformity.
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Leri-Weill Dyschondrosteosis
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nord_715_5
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Diagnosis of Leri-Weill Dyschondrosteosis
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A diagnosis is based upon a thorough clinical examination and identification of characteristic physical findings. A diagnosis can be difficult because certain symptoms may not be apparent until puberty. X-ray studies (radiographs), in particular a wrist X-ray, can reveal characteristic changes to the affected bones. Molecular genetic testing can confirm a diagnosis of LWD in approximately 70% of cases. Molecular genetic testing can detect genetic alterations in SHOX and/or its regulatory elements, known to cause the disorder.
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Diagnosis of Leri-Weill Dyschondrosteosis. A diagnosis is based upon a thorough clinical examination and identification of characteristic physical findings. A diagnosis can be difficult because certain symptoms may not be apparent until puberty. X-ray studies (radiographs), in particular a wrist X-ray, can reveal characteristic changes to the affected bones. Molecular genetic testing can confirm a diagnosis of LWD in approximately 70% of cases. Molecular genetic testing can detect genetic alterations in SHOX and/or its regulatory elements, known to cause the disorder.
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Leri-Weill Dyschondrosteosis
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nord_715_6
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Therapies of Leri-Weill Dyschondrosteosis
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The treatment of LWD is symptomatic and supportive. Growth hormone therapy may be recommended for children who have not reached puberty in order to improve their childhood and adult height. According to the medical literature, a benefit of 7 to 10 centimeters (approximately 3 to 4 inches) to final height can be achieved. The skeletal defects do not worsen with treatment.Madelung deformity may not require any therapy or only conservative therapy such as wrist splints or supports, particularly during periods of increased discomfort. The use of ergonomic devices designed to help the wrist may be of benefit. If Madelung deformity causes pain or discomfort, activities that strain the wrist should be limited. Some individuals may have severe Madelung deformity and require orthopedic surgery to alleviate the pain and improve mobility.Bone growth in individuals with LWD should be monitored regularly by a physician during the growth years.Genetic counseling is recommended for affected individuals and their families.
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Therapies of Leri-Weill Dyschondrosteosis. The treatment of LWD is symptomatic and supportive. Growth hormone therapy may be recommended for children who have not reached puberty in order to improve their childhood and adult height. According to the medical literature, a benefit of 7 to 10 centimeters (approximately 3 to 4 inches) to final height can be achieved. The skeletal defects do not worsen with treatment.Madelung deformity may not require any therapy or only conservative therapy such as wrist splints or supports, particularly during periods of increased discomfort. The use of ergonomic devices designed to help the wrist may be of benefit. If Madelung deformity causes pain or discomfort, activities that strain the wrist should be limited. Some individuals may have severe Madelung deformity and require orthopedic surgery to alleviate the pain and improve mobility.Bone growth in individuals with LWD should be monitored regularly by a physician during the growth years.Genetic counseling is recommended for affected individuals and their families.
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Leri-Weill Dyschondrosteosis
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nord_716_0
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Overview of Lesch Nyhan Syndrome
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Lesch-Nyhan syndrome is a rare inborn error of purine metabolism characterized by the absence or deficiency of the activity of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Purines are nitrogen-containing compounds found in many foods (e.g., organ meats, poultry, and legumes). In the absence of HPRT, the purines hypoxanthine and guanine are not built into nucleotides. Uric acid levels are abnormally high in people with Lesch-Nyhan syndrome and sodium urate crystals may abnormally accumulate in the joints and kidneys. Lesch-Nyhan syndrome is inherited as an X-linked recessive genetic disorder that, with rare female exceptions, most often affects males. The symptoms of Lesch-Nyhan syndrome include impaired kidney function, acute gouty arthritis, and self-mutilating behaviors such as lip and finger biting and/or head banging. Additional symptoms include involuntary muscle movements, and neurological impairment.
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Overview of Lesch Nyhan Syndrome. Lesch-Nyhan syndrome is a rare inborn error of purine metabolism characterized by the absence or deficiency of the activity of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Purines are nitrogen-containing compounds found in many foods (e.g., organ meats, poultry, and legumes). In the absence of HPRT, the purines hypoxanthine and guanine are not built into nucleotides. Uric acid levels are abnormally high in people with Lesch-Nyhan syndrome and sodium urate crystals may abnormally accumulate in the joints and kidneys. Lesch-Nyhan syndrome is inherited as an X-linked recessive genetic disorder that, with rare female exceptions, most often affects males. The symptoms of Lesch-Nyhan syndrome include impaired kidney function, acute gouty arthritis, and self-mutilating behaviors such as lip and finger biting and/or head banging. Additional symptoms include involuntary muscle movements, and neurological impairment.
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Lesch Nyhan Syndrome
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nord_716_1
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Symptoms of Lesch Nyhan Syndrome
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The symptoms of Lesch-Nyhan syndrome may become apparent as early as six months of age. Earlier urate crystal formation, resulting from abnormally increased levels of uric acid in the urine, leads to the presence of orange colored deposits (“orange sand”) in the diapers of infants with this disorder. This may be the first manifestation of Lesch-Nyhan syndrome, but it is seldom recognized in early infancy.Urate stones may develop in the kidneys of infants with Lesch-Nyhan syndrome as a result of excessive amounts of uric acid that are excreted as sodium urate. These stones may cause blood to appear in the urine (hematuria) and increase the risk of urinary tract infections. Urate crystals may also be found in the joints, but in general, it is not until the late teens or adulthood that untreated patients with Lesch-Nyhan syndrome experience recurring episodes of pain and swelling of the joints, just like those of adults with gout. These episodes may become progressively more frequent once they begin.In older children with this disorder, deposits of sodium urate may collect in cartilaginous tissues in joints and in the ears; in the ears, they form visible “bulges” called tophi. This is the picture commonly known as gout.Neurological symptoms associated with Lesch-Nyhan syndrome usually begin before the age of 12 months. These may include involuntary writhing movements of the arms and legs (dystonia) and purposeless repetitive movements (chorea) such as flexing of the fingers, raising and lowering of the shoulders, and/or facial grimacing. Infants who had previously been able to sit upright typically lose this ability. Initially, muscles may be soft (hypotonia) and lead to difficulty in holding the head in an upright position. Affected infants may fail to reach developmental milestones such as crawling, sitting or walking (developmental delay). Eventually, most children with Lesch-Nyhan syndrome experience abnormally increased muscle tone (hypertonia) and muscle rigidity (spasticity). Deep tendon reflexes are increased (hyperreflexia). Intellectual disability may also occur and is typically moderate. However, accurate evaluation of intelligence may be difficult because of poorly articulated speech (dysarthria). Some patients have normal intelligence.The most striking feature of Lesch-Nyhan syndrome, which has been observed in approximately 85 percent of patients, is self-mutilation. These behaviors most often begin between the ages of two and three years. However, they can also develop during the first year of life or much later during childhood. Self-injurious behavior may include repeated biting of the lips, fingers, and/or hands, and repetitive banging of the head against hard objects. Some children may scratch their face repeatedly. However, individuals with Lesch-Nyhan syndrome are not insensitive to pain. Additional behavioral abnormalities include aggressiveness, vomiting, and spitting. Self-mutilating behaviors regularly lead to loss of tissue.Children with Lesch-Nyhan syndrome may have difficulty swallowing (dysphagia) and may be difficult to feed. Vomiting is common, and most affected children are underweight for their age. Additional symptoms may include irritability or screaming. Some children with Lesch-Nyhan syndrome may also develop a rare anemia known as megaloblastic anemia. (For more information on megaloblastic anemia, see the Related Disorders section of this report.)Another symptom of Lesch-Nyhan syndrome may be a severe muscle spasm that causes the back to arch severely and the head and heels to bend backward (opisthotonos). Affected children may also experience hip dislocation, fractures, abnormal curvature of the spine (scoliosis) and/or permanent fixation of several joints in a flexed position (contractures).Female carriers usually do not have symptoms of the disorder, but may develop gout later in life as a result of untreated excess uric acid in the blood (hyperuricemia).
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Symptoms of Lesch Nyhan Syndrome. The symptoms of Lesch-Nyhan syndrome may become apparent as early as six months of age. Earlier urate crystal formation, resulting from abnormally increased levels of uric acid in the urine, leads to the presence of orange colored deposits (“orange sand”) in the diapers of infants with this disorder. This may be the first manifestation of Lesch-Nyhan syndrome, but it is seldom recognized in early infancy.Urate stones may develop in the kidneys of infants with Lesch-Nyhan syndrome as a result of excessive amounts of uric acid that are excreted as sodium urate. These stones may cause blood to appear in the urine (hematuria) and increase the risk of urinary tract infections. Urate crystals may also be found in the joints, but in general, it is not until the late teens or adulthood that untreated patients with Lesch-Nyhan syndrome experience recurring episodes of pain and swelling of the joints, just like those of adults with gout. These episodes may become progressively more frequent once they begin.In older children with this disorder, deposits of sodium urate may collect in cartilaginous tissues in joints and in the ears; in the ears, they form visible “bulges” called tophi. This is the picture commonly known as gout.Neurological symptoms associated with Lesch-Nyhan syndrome usually begin before the age of 12 months. These may include involuntary writhing movements of the arms and legs (dystonia) and purposeless repetitive movements (chorea) such as flexing of the fingers, raising and lowering of the shoulders, and/or facial grimacing. Infants who had previously been able to sit upright typically lose this ability. Initially, muscles may be soft (hypotonia) and lead to difficulty in holding the head in an upright position. Affected infants may fail to reach developmental milestones such as crawling, sitting or walking (developmental delay). Eventually, most children with Lesch-Nyhan syndrome experience abnormally increased muscle tone (hypertonia) and muscle rigidity (spasticity). Deep tendon reflexes are increased (hyperreflexia). Intellectual disability may also occur and is typically moderate. However, accurate evaluation of intelligence may be difficult because of poorly articulated speech (dysarthria). Some patients have normal intelligence.The most striking feature of Lesch-Nyhan syndrome, which has been observed in approximately 85 percent of patients, is self-mutilation. These behaviors most often begin between the ages of two and three years. However, they can also develop during the first year of life or much later during childhood. Self-injurious behavior may include repeated biting of the lips, fingers, and/or hands, and repetitive banging of the head against hard objects. Some children may scratch their face repeatedly. However, individuals with Lesch-Nyhan syndrome are not insensitive to pain. Additional behavioral abnormalities include aggressiveness, vomiting, and spitting. Self-mutilating behaviors regularly lead to loss of tissue.Children with Lesch-Nyhan syndrome may have difficulty swallowing (dysphagia) and may be difficult to feed. Vomiting is common, and most affected children are underweight for their age. Additional symptoms may include irritability or screaming. Some children with Lesch-Nyhan syndrome may also develop a rare anemia known as megaloblastic anemia. (For more information on megaloblastic anemia, see the Related Disorders section of this report.)Another symptom of Lesch-Nyhan syndrome may be a severe muscle spasm that causes the back to arch severely and the head and heels to bend backward (opisthotonos). Affected children may also experience hip dislocation, fractures, abnormal curvature of the spine (scoliosis) and/or permanent fixation of several joints in a flexed position (contractures).Female carriers usually do not have symptoms of the disorder, but may develop gout later in life as a result of untreated excess uric acid in the blood (hyperuricemia).
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Causes of Lesch Nyhan Syndrome
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The only gene known to be associated with Lesch-Nyhan syndrome is located on the X chromosome and called HPRT1. Abnormalities (mutations) in the HPRT1 gene result in the absence or deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT) and the abnormal accumulation of uric acid in the blood.Lesch-Nyhan syndrome is inherited in an X-linked pattern. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an abnormal gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the abnormal gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the abnormal gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Causes of Lesch Nyhan Syndrome. The only gene known to be associated with Lesch-Nyhan syndrome is located on the X chromosome and called HPRT1. Abnormalities (mutations) in the HPRT1 gene result in the absence or deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT) and the abnormal accumulation of uric acid in the blood.Lesch-Nyhan syndrome is inherited in an X-linked pattern. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an abnormal gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the abnormal gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. If a male with an X-linked disorder is able to reproduce, he will pass the abnormal gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Affects of Lesch Nyhan Syndrome
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Lesch-Nyhan syndrome is a rare disorder that affects males. Rarely, females may be affected by the disorder. However, in most cases, females may be carriers of the disease gene, but do not exhibit any symptoms. According to one estimate, the disorder occurs at the rate of approximately one in 380,000 births in the United States.
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Affects of Lesch Nyhan Syndrome. Lesch-Nyhan syndrome is a rare disorder that affects males. Rarely, females may be affected by the disorder. However, in most cases, females may be carriers of the disease gene, but do not exhibit any symptoms. According to one estimate, the disorder occurs at the rate of approximately one in 380,000 births in the United States.
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Related disorders of Lesch Nyhan Syndrome
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Symptoms of the following disorders can be similar to those of Lesch-Nyhan syndrome in the sense that self-injurious behavior may occur. Comparisons may be useful for a differential diagnosis:Familial dysautonomia is a rare genetic disorder of the autonomic nervous system that primarily affects people of Eastern European Jewish heritage. It is characterized by diminished sensitivity to pain, lack of overflow tearing in the eyes, a decrease in the number of knob-like projections that cover the tongue (fungiform papillae), unusual fluctuations of body temperature, and unstable blood pressure. Symptoms of this disorder are apparent at birth. The autonomic nervous system controls vital involuntary body functions. (For more information on this disorder, choose “familial dysautonomia” as your search term in the Rare Disease Database.)Cornelia de Lange syndrome is a rare genetic disorder that is apparent at birth. Associated symptoms and findings typically include delays in physical development before and after birth; characteristic abnormalities of the head and facial (craniofacial) area, resulting in a distinctive facial appearance; malformations of the hands and arms (upper limbs); and mild to severe intellectual disability. Infants with Cornelia de Lange syndrome may also have feeding and breathing difficulties; an increased susceptibility to respiratory infections; a low-pitched “growling” cry; heart defects; delayed skeletal maturation; hearing loss; or other physical abnormalities. The range and severity of associated symptoms and findings may be extremely variable from person to person. (For more information on this disorder, choose “Cornelia de Lange” as your search term in the Rare Disease Database.)
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Related disorders of Lesch Nyhan Syndrome. Symptoms of the following disorders can be similar to those of Lesch-Nyhan syndrome in the sense that self-injurious behavior may occur. Comparisons may be useful for a differential diagnosis:Familial dysautonomia is a rare genetic disorder of the autonomic nervous system that primarily affects people of Eastern European Jewish heritage. It is characterized by diminished sensitivity to pain, lack of overflow tearing in the eyes, a decrease in the number of knob-like projections that cover the tongue (fungiform papillae), unusual fluctuations of body temperature, and unstable blood pressure. Symptoms of this disorder are apparent at birth. The autonomic nervous system controls vital involuntary body functions. (For more information on this disorder, choose “familial dysautonomia” as your search term in the Rare Disease Database.)Cornelia de Lange syndrome is a rare genetic disorder that is apparent at birth. Associated symptoms and findings typically include delays in physical development before and after birth; characteristic abnormalities of the head and facial (craniofacial) area, resulting in a distinctive facial appearance; malformations of the hands and arms (upper limbs); and mild to severe intellectual disability. Infants with Cornelia de Lange syndrome may also have feeding and breathing difficulties; an increased susceptibility to respiratory infections; a low-pitched “growling” cry; heart defects; delayed skeletal maturation; hearing loss; or other physical abnormalities. The range and severity of associated symptoms and findings may be extremely variable from person to person. (For more information on this disorder, choose “Cornelia de Lange” as your search term in the Rare Disease Database.)
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Diagnosis of Lesch Nyhan Syndrome
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The diagnosis of Lesch-Nyhan syndrome may be confirmed by a thorough clinical evaluation, including a detailed patient history and specialized blood tests. Children with this disorder have abnormally high concentrations of uric acid in the blood. The absence of the HPRT enzyme in cells from any tissue confirms the diagnosis. Molecular genetic testing for the HPRT1 gene is available to determine the specific disease-causing mutation. Carrier testing for Lesch-Nyhan syndrome is possible using molecular genetic testing.Prenatal diagnosis and preimplantation genetic diagnosis are possible if the disease-causing HPRT1 gene mutation has been identified in an affected family member. Prenatal diagnosis can also be done by enzyme analysis.
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Diagnosis of Lesch Nyhan Syndrome. The diagnosis of Lesch-Nyhan syndrome may be confirmed by a thorough clinical evaluation, including a detailed patient history and specialized blood tests. Children with this disorder have abnormally high concentrations of uric acid in the blood. The absence of the HPRT enzyme in cells from any tissue confirms the diagnosis. Molecular genetic testing for the HPRT1 gene is available to determine the specific disease-causing mutation. Carrier testing for Lesch-Nyhan syndrome is possible using molecular genetic testing.Prenatal diagnosis and preimplantation genetic diagnosis are possible if the disease-causing HPRT1 gene mutation has been identified in an affected family member. Prenatal diagnosis can also be done by enzyme analysis.
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Therapies of Lesch Nyhan Syndrome
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Treatment
The treatment of Lesch-Nyhan 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, specialists who diagnose and treat skeletal disorders (orthopedists), physical therapists, and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.The drug allopurinol is used to control the excessive amounts of uric acid associated with Lesch-Nyhan syndrome and control symptoms associated with excessive amounts of uric acid. However, this treatment has no effect on the neurological or behavioral symptoms associated with this disorder.When kidney stones are present, they may be treated with extracorporeal shock wave lithotripsy (ESWL). During this procedure, the patient is immersed in water and high energy shock waves are directed to the body in the area of the kidney stone. The stone dissolves into small pieces, and these fragments are passed with the urine.No sustained treatment or drug therapy has proven uniformly effective for the treatment of the neurological problems associated with Lesch-Nyhan syndrome. Baclofen or benzodiazepines have been used to treat spasticity. Diazepam may be useful.Individuals with Lesch-Nyhan syndrome have been reported to benefit from behavior modification techniques designed to reduce self-mutilating behaviors, but real success is unusual. Children with Lesch-Nyhan syndrome usually require physical restraint at the hips, chest, and elbows so they do not injure themselves. Elbow restraints keep the hands free. Biting of fingers and/or lips, which can lead to permanent disfigurement, may be prevented by the use of a mouth guard (oral prosthetic) or the removal of the teeth. Many affected individuals request restraints themselves. With advancing age, some affected individuals’ self-mutilating behaviors may improve or cease.In some patients, drugs have been used to treat behavioral abnormalities associated with Lesch-Nyhan syndrome. These include Depakote (sodium valproate), Gabapentin, baclofen, and carbamazepine. Benzodiazepines may be beneficial in treating anxiety symptoms sometimes associated with Lesch-Nyhan syndrome.Genetic counseling is recommended for families with children who have Lesch-Nyhan syndrome. Other treatment is symptomatic and supportive.
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Therapies of Lesch Nyhan Syndrome. Treatment
The treatment of Lesch-Nyhan 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, specialists who diagnose and treat skeletal disorders (orthopedists), physical therapists, and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.The drug allopurinol is used to control the excessive amounts of uric acid associated with Lesch-Nyhan syndrome and control symptoms associated with excessive amounts of uric acid. However, this treatment has no effect on the neurological or behavioral symptoms associated with this disorder.When kidney stones are present, they may be treated with extracorporeal shock wave lithotripsy (ESWL). During this procedure, the patient is immersed in water and high energy shock waves are directed to the body in the area of the kidney stone. The stone dissolves into small pieces, and these fragments are passed with the urine.No sustained treatment or drug therapy has proven uniformly effective for the treatment of the neurological problems associated with Lesch-Nyhan syndrome. Baclofen or benzodiazepines have been used to treat spasticity. Diazepam may be useful.Individuals with Lesch-Nyhan syndrome have been reported to benefit from behavior modification techniques designed to reduce self-mutilating behaviors, but real success is unusual. Children with Lesch-Nyhan syndrome usually require physical restraint at the hips, chest, and elbows so they do not injure themselves. Elbow restraints keep the hands free. Biting of fingers and/or lips, which can lead to permanent disfigurement, may be prevented by the use of a mouth guard (oral prosthetic) or the removal of the teeth. Many affected individuals request restraints themselves. With advancing age, some affected individuals’ self-mutilating behaviors may improve or cease.In some patients, drugs have been used to treat behavioral abnormalities associated with Lesch-Nyhan syndrome. These include Depakote (sodium valproate), Gabapentin, baclofen, and carbamazepine. Benzodiazepines may be beneficial in treating anxiety symptoms sometimes associated with Lesch-Nyhan syndrome.Genetic counseling is recommended for families with children who have Lesch-Nyhan syndrome. Other treatment is symptomatic and supportive.
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Overview of Leukocyte Adhesion Deficiency Syndromes
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Leukocyte adhesions deficiency (LAD) syndromes are a group of rare disorders affecting the immune system. LAD syndromes are characterized by defects affecting how white blood cells (leukocytes) respond and travel to the site of a wound or infection. Three distinct types of leukocyte adhesion syndrome have been identified. The specific symptoms and the severity of LAD syndromes vary from one person to another. All affected individuals develop an increased susceptibility to developing recurrent bacterial and fungal infections. Additional symptoms may occur depending upon the specific subtype present. LAD syndromes are caused by mutations of specific genes that contain instructions for creating certain proteins that are necessary for white blood cells to travel from the bloodstream to the site of an infection or inflammation. Individuals with severe forms of LAD may have near complete absence of these proteins. Individuals who have milder forms of LAD syndromes have deficient levels of these proteins, but retain some residual protein activity.
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Overview of Leukocyte Adhesion Deficiency Syndromes. Leukocyte adhesions deficiency (LAD) syndromes are a group of rare disorders affecting the immune system. LAD syndromes are characterized by defects affecting how white blood cells (leukocytes) respond and travel to the site of a wound or infection. Three distinct types of leukocyte adhesion syndrome have been identified. The specific symptoms and the severity of LAD syndromes vary from one person to another. All affected individuals develop an increased susceptibility to developing recurrent bacterial and fungal infections. Additional symptoms may occur depending upon the specific subtype present. LAD syndromes are caused by mutations of specific genes that contain instructions for creating certain proteins that are necessary for white blood cells to travel from the bloodstream to the site of an infection or inflammation. Individuals with severe forms of LAD may have near complete absence of these proteins. Individuals who have milder forms of LAD syndromes have deficient levels of these proteins, but retain some residual protein activity.
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Symptoms of Leukocyte Adhesion Deficiency Syndromes
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The symptoms of LAD syndromes can vary greatly from one person to another based upon the subtype present, the amount of residual protein activity and additional factors. The LAD syndromes are primary immunodeficiency disorders that cause individuals to be abnormally susceptible to developing infections. Affected individuals also have elevated levels of white blood cells (leukocytosis).LEUKOCYTE ADHESION DEFICIENCY TYPE I
The symptoms of LAD I can vary from one to person to another. Some individuals have a severe form of the disorder that can cause life-threatening complications; other individuals have a milder form. LAD I is usually characterized by recurrent, often severe, bacterial infections, and delayed detachment of the umbilical cord. Fungal infections are also common. Bacterial and fungal infections most often affect the skin and mucous membranes (mucosal surfaces). The absence of pus formation at the site of infection is an important feature that can indicate a leukocyte adhesion deficiency. Delayed detachment of the umbilical cord often occurs along with infection of the umbilical cord stump (omphalitis). Recurrent, bacterial infections usually develop shortly after birth in LAD I and can cause life-threatening complications in many cases. Individuals with the milder form of LAD I have fewer and less severe infections.After infancy, affected children may develop progressive inflammation of the tissues that surround and support the teeth (periodontitis) and inflammation of the gums (gingivitis). Periodontitis can eventually cause tooth loss. Wounds either from surgery or trauma are slow to heal (delayed wound healing) and may be more likely to scar. Affected individuals may also develop sores in the area surrounding.LEUKOCYTE ADHESION DEFICIENCY TYPE II
Infants with LAD II develop recurrent, bacterial infections. However, the infections and their complications are usually milder than those seen in infants with LAD I. Pneumonia, chronic middle ear infections (otitis media), infection of the tissues that surround and support the teeth (periodontitis) and localized infection of the tissue underneath the surface of the skin (cellulitis) commonly occur in LAD II. The infections are usually not life-threatening and are often treated in an outpatient basis. No pus formation is seen at the site of infection. Generally, the frequency of infections in LAD II decreases after affected individuals reach three years of age. As affected individuals grow older, severe periodontitis is the main infectious complication.Unlike LAD I, infants with LAD II do not experience a delay in the separation of the umbilical cord. Individuals with LAD II do have additional complications not seen in LAD I including a unique blood type called the Bombay (hh) blood type. Additional features that characterize LAD II include diminished muscle tone resulting in floppiness (hypotonia), distinctive facial features, severe mental retardation and severe growth deficiencies resulting in short stature.LAD II may also be known as congenital disorder of glycosylation type IIc due to the primary defect in fucose metabolism.LEUKOCYTE ADHESION DEFICIENCY TYPE III
Individuals with LAD III have recurrent bacterial and fungal infections that follow a similar course of infection as seen in individuals with LAD I. However, these affected individuals also have a bleeding tendency that can cause life-threatening complications. The bleeding complication of LAD III resembles a rare disorder known as Glanzmann thrombasthenia, which is characterized by impaired function of blood cells required for clotting (platelets). Affected individuals have a tendency to bleed easily and profusely especially after surgical procedures. Other symptoms may include susceptibility to easy bruising, nosebleeds (epistaxis), bleeding from the gums (gingival), and/or large red or purple colored spots on the skin that are caused by bleeding under the skin (subcutaneous). The bleeding problem usually starts at birth.Individuals who were once classified as having LAD I variant (because of the similar disease expression) are now considered to have LAD III because the underlying genetic cause of LAD III is different from the underlying genetic cause of LAD I.
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Symptoms of Leukocyte Adhesion Deficiency Syndromes. The symptoms of LAD syndromes can vary greatly from one person to another based upon the subtype present, the amount of residual protein activity and additional factors. The LAD syndromes are primary immunodeficiency disorders that cause individuals to be abnormally susceptible to developing infections. Affected individuals also have elevated levels of white blood cells (leukocytosis).LEUKOCYTE ADHESION DEFICIENCY TYPE I
The symptoms of LAD I can vary from one to person to another. Some individuals have a severe form of the disorder that can cause life-threatening complications; other individuals have a milder form. LAD I is usually characterized by recurrent, often severe, bacterial infections, and delayed detachment of the umbilical cord. Fungal infections are also common. Bacterial and fungal infections most often affect the skin and mucous membranes (mucosal surfaces). The absence of pus formation at the site of infection is an important feature that can indicate a leukocyte adhesion deficiency. Delayed detachment of the umbilical cord often occurs along with infection of the umbilical cord stump (omphalitis). Recurrent, bacterial infections usually develop shortly after birth in LAD I and can cause life-threatening complications in many cases. Individuals with the milder form of LAD I have fewer and less severe infections.After infancy, affected children may develop progressive inflammation of the tissues that surround and support the teeth (periodontitis) and inflammation of the gums (gingivitis). Periodontitis can eventually cause tooth loss. Wounds either from surgery or trauma are slow to heal (delayed wound healing) and may be more likely to scar. Affected individuals may also develop sores in the area surrounding.LEUKOCYTE ADHESION DEFICIENCY TYPE II
Infants with LAD II develop recurrent, bacterial infections. However, the infections and their complications are usually milder than those seen in infants with LAD I. Pneumonia, chronic middle ear infections (otitis media), infection of the tissues that surround and support the teeth (periodontitis) and localized infection of the tissue underneath the surface of the skin (cellulitis) commonly occur in LAD II. The infections are usually not life-threatening and are often treated in an outpatient basis. No pus formation is seen at the site of infection. Generally, the frequency of infections in LAD II decreases after affected individuals reach three years of age. As affected individuals grow older, severe periodontitis is the main infectious complication.Unlike LAD I, infants with LAD II do not experience a delay in the separation of the umbilical cord. Individuals with LAD II do have additional complications not seen in LAD I including a unique blood type called the Bombay (hh) blood type. Additional features that characterize LAD II include diminished muscle tone resulting in floppiness (hypotonia), distinctive facial features, severe mental retardation and severe growth deficiencies resulting in short stature.LAD II may also be known as congenital disorder of glycosylation type IIc due to the primary defect in fucose metabolism.LEUKOCYTE ADHESION DEFICIENCY TYPE III
Individuals with LAD III have recurrent bacterial and fungal infections that follow a similar course of infection as seen in individuals with LAD I. However, these affected individuals also have a bleeding tendency that can cause life-threatening complications. The bleeding complication of LAD III resembles a rare disorder known as Glanzmann thrombasthenia, which is characterized by impaired function of blood cells required for clotting (platelets). Affected individuals have a tendency to bleed easily and profusely especially after surgical procedures. Other symptoms may include susceptibility to easy bruising, nosebleeds (epistaxis), bleeding from the gums (gingival), and/or large red or purple colored spots on the skin that are caused by bleeding under the skin (subcutaneous). The bleeding problem usually starts at birth.Individuals who were once classified as having LAD I variant (because of the similar disease expression) are now considered to have LAD III because the underlying genetic cause of LAD III is different from the underlying genetic cause of LAD I.
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Causes of Leukocyte Adhesion Deficiency Syndromes
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Leukocyte adhesion syndromes are rare, genetic disorders. LAD I is caused by mutations of the ITGB2 gene. LAD II is caused by mutations of the SLC35C1 gene. The genetic defect in LAD III is a mutation in the gene for Kindlin 3, a protein essential for all integrins activation. Lack of integrins activation affects the ability of leukocytes and platelets to bind to the endothelium. In some cases, there is also a mutation in the gene for CalDAGGEF1, another protein important in integrins activation.The mutations that cause LAD I, LAD II and III are each inherited as autosomal recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. LAD syndromes are classified as a primary immunodeficiency disorders. The immune system protects the body from bacteria, viruses, parasites and other foreign, harmful substances. White blood cells (leukocytes) are part of the immune system. White blood cells continually look for signs of disease, infection or injury. Normally, white blood cells circulate in the bloodstream. When they detect an infection or foreign substance, white blood cells race to the site of infection or inflammation to protect the body. White blood cells may destroy foreign material by ingesting it themselves or producing unique antibodies that destroy harmful material. A specific type of white blood cell, called a neutrophil, is most often affected in LAD syndromes. The main role of neutrophils is to defend the body against bacteria and fungi.White blood cells travel (migrate) to the site of inflammation or infection in the body through a complex process sometimes referred to as the adhesion cascade. This process requires several, precise steps. These steps include the tethering of white blood cells to the thin layer of cells that line the inside surface of blood vessels (endothelium), the rolling of white blood cells along the endothelium, leukocyte activation and the eventual attachment (adhesion) of white blood cells directly to the endothelium. Ultimately, white blood cells move from the endothelium through the blood vessel wall and into the surrounding tissue, eventually traveling to the site of an infection or inflammation to protect the body.Specific chemicals such as proteins are necessary for white blood cells to be able to tether, roll along and stick (adhere) to the endothelium. Individuals with LAD syndromes do not have sufficient levels of these proteins and their white blood cells cannot tether, roll along or fail to stick to the endothelium. Therefore, the white blood cells of individuals with LAD syndromes fail to reach the site of infection or inflammation.The ITGB2 gene, which causes LAD I, contains instructions for creating (encoding) a protein known as CD18. CD18 is a subunit of integrin or a cell surface protein and is normally found on the surface of white blood cells. Mutations of the ITGB2 gene result in defective CD18 or deficient levels of CD18. Without sufficient levels of functional CD18, white blood cells cannot stick (adhere) to the endothelium. In rare cases, CD18 is expressed normally but because of a specific ITGB2 mutation, the protein is nonfunctional. These cases are referred to as LAD I variant.Specific proteins are also necessary for white blood cells to roll along the endothelium. Individuals with LAD II do not have sufficient levels of these proteins. The SLC35C1 gene contains instructions for creating (encoding) an enzyme (GPD-fucose transporter) that is required to transport a specific sugar (fucose) in the body. Fucose is necessary for a carbohydrate structure known as CD15 (sialyl Lewis x antigen) to bind to a type of protein (glycoprotein) called selectin found on the endothelium. This process is required for white blood cells to be able to roll along the endothelium. Since white blood cells cannot roll along the endothelium in LAD II, they are unable to stick to the endothelium and fail to travel to the site of infection and inflammation.
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Causes of Leukocyte Adhesion Deficiency Syndromes. Leukocyte adhesion syndromes are rare, genetic disorders. LAD I is caused by mutations of the ITGB2 gene. LAD II is caused by mutations of the SLC35C1 gene. The genetic defect in LAD III is a mutation in the gene for Kindlin 3, a protein essential for all integrins activation. Lack of integrins activation affects the ability of leukocytes and platelets to bind to the endothelium. In some cases, there is also a mutation in the gene for CalDAGGEF1, another protein important in integrins activation.The mutations that cause LAD I, LAD II and III are each inherited as autosomal recessive traits. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder. LAD syndromes are classified as a primary immunodeficiency disorders. The immune system protects the body from bacteria, viruses, parasites and other foreign, harmful substances. White blood cells (leukocytes) are part of the immune system. White blood cells continually look for signs of disease, infection or injury. Normally, white blood cells circulate in the bloodstream. When they detect an infection or foreign substance, white blood cells race to the site of infection or inflammation to protect the body. White blood cells may destroy foreign material by ingesting it themselves or producing unique antibodies that destroy harmful material. A specific type of white blood cell, called a neutrophil, is most often affected in LAD syndromes. The main role of neutrophils is to defend the body against bacteria and fungi.White blood cells travel (migrate) to the site of inflammation or infection in the body through a complex process sometimes referred to as the adhesion cascade. This process requires several, precise steps. These steps include the tethering of white blood cells to the thin layer of cells that line the inside surface of blood vessels (endothelium), the rolling of white blood cells along the endothelium, leukocyte activation and the eventual attachment (adhesion) of white blood cells directly to the endothelium. Ultimately, white blood cells move from the endothelium through the blood vessel wall and into the surrounding tissue, eventually traveling to the site of an infection or inflammation to protect the body.Specific chemicals such as proteins are necessary for white blood cells to be able to tether, roll along and stick (adhere) to the endothelium. Individuals with LAD syndromes do not have sufficient levels of these proteins and their white blood cells cannot tether, roll along or fail to stick to the endothelium. Therefore, the white blood cells of individuals with LAD syndromes fail to reach the site of infection or inflammation.The ITGB2 gene, which causes LAD I, contains instructions for creating (encoding) a protein known as CD18. CD18 is a subunit of integrin or a cell surface protein and is normally found on the surface of white blood cells. Mutations of the ITGB2 gene result in defective CD18 or deficient levels of CD18. Without sufficient levels of functional CD18, white blood cells cannot stick (adhere) to the endothelium. In rare cases, CD18 is expressed normally but because of a specific ITGB2 mutation, the protein is nonfunctional. These cases are referred to as LAD I variant.Specific proteins are also necessary for white blood cells to roll along the endothelium. Individuals with LAD II do not have sufficient levels of these proteins. The SLC35C1 gene contains instructions for creating (encoding) an enzyme (GPD-fucose transporter) that is required to transport a specific sugar (fucose) in the body. Fucose is necessary for a carbohydrate structure known as CD15 (sialyl Lewis x antigen) to bind to a type of protein (glycoprotein) called selectin found on the endothelium. This process is required for white blood cells to be able to roll along the endothelium. Since white blood cells cannot roll along the endothelium in LAD II, they are unable to stick to the endothelium and fail to travel to the site of infection and inflammation.
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Affects of Leukocyte Adhesion Deficiency Syndromes
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LAD syndromes affect males and females in equal numbers. The exact incidence of these disorders in the general population is unknown. LAD I is by far the more common one with several hundreds of patients reported in the medical literature from all over the world. LAD II is very rare reported in less than 10 patients and LAD III is also rare with 25 patients mainly from the Middle East region. These disorders often go unrecognized and may be misdiagnosed, making it difficult to determine their true frequency in the general population. LAD I was first described in the medical literature in 1979. LAD II was first reported in 1992. LAD III was first reported in 1997.
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Affects of Leukocyte Adhesion Deficiency Syndromes. LAD syndromes affect males and females in equal numbers. The exact incidence of these disorders in the general population is unknown. LAD I is by far the more common one with several hundreds of patients reported in the medical literature from all over the world. LAD II is very rare reported in less than 10 patients and LAD III is also rare with 25 patients mainly from the Middle East region. These disorders often go unrecognized and may be misdiagnosed, making it difficult to determine their true frequency in the general population. LAD I was first described in the medical literature in 1979. LAD II was first reported in 1992. LAD III was first reported in 1997.
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Related disorders of Leukocyte Adhesion Deficiency Syndromes
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Symptoms of the following disorders can be similar to those of LAD syndromes. Comparisons may be useful for a differential diagnosis.The specific symptoms and laboratory findings associated with the LAD syndromes are usually enough to distinguish these disorders from other similar disorders. Other causes of elevated white blood cells (leukocytosis) should be ruled out. Related primary immunodeficiency disorders such as chronic granulomatous disease or the hyper IgE syndromes can be distinguished from LAD syndromes because the clinical features of infection are different. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Leukocyte Adhesion Deficiency Syndromes. Symptoms of the following disorders can be similar to those of LAD syndromes. Comparisons may be useful for a differential diagnosis.The specific symptoms and laboratory findings associated with the LAD syndromes are usually enough to distinguish these disorders from other similar disorders. Other causes of elevated white blood cells (leukocytosis) should be ruled out. Related primary immunodeficiency disorders such as chronic granulomatous disease or the hyper IgE syndromes can be distinguished from LAD syndromes because the clinical features of infection are different. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Diagnosis of Leukocyte Adhesion Deficiency Syndromes
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A diagnosis of a LAD syndrome is suspected based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of tests such as a complete blood count (CBC). A CBC can detect elevated levels of a type of white blood cell known as a neutrophil (neutrophilia) and also lymphocytes. A diagnosis of LAD I should be ruled out in any infant with recurrent soft tissue infections and a very high white blood cell count (leukocytosis).A diagnosis of LAD I or LAD II or III can be confirmed through molecular genetic testing, which can reveal the characteristic mutations of the ITGB2, the SLC35C1 or the FERMT3 genes that cause these disorders. Molecular genetic testing is available on a clinical basis.Diagnosis before birth (prenatal diagnosis) is possible in families where the exact molecular defect has already been identified. A test known as chorionic villi biopsy is performed. Chorionic villi are thin, hair-like structures found on the placenta. Chorionic villi cells contain the same genetic material found in the cells of the fetus. A sample of tissue is taken from the placenta and studied to detect the presence of the specific genetic mutation that has caused LAD I, LAD II or LAD III in that family. LAD II can also be detected before birth by identifying the characteristic blood type (Bombay blood phenotype) associated with the disorder. This is possible at approximately 20 weeks gestation.
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Diagnosis of Leukocyte Adhesion Deficiency Syndromes. A diagnosis of a LAD syndrome is suspected based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of tests such as a complete blood count (CBC). A CBC can detect elevated levels of a type of white blood cell known as a neutrophil (neutrophilia) and also lymphocytes. A diagnosis of LAD I should be ruled out in any infant with recurrent soft tissue infections and a very high white blood cell count (leukocytosis).A diagnosis of LAD I or LAD II or III can be confirmed through molecular genetic testing, which can reveal the characteristic mutations of the ITGB2, the SLC35C1 or the FERMT3 genes that cause these disorders. Molecular genetic testing is available on a clinical basis.Diagnosis before birth (prenatal diagnosis) is possible in families where the exact molecular defect has already been identified. A test known as chorionic villi biopsy is performed. Chorionic villi are thin, hair-like structures found on the placenta. Chorionic villi cells contain the same genetic material found in the cells of the fetus. A sample of tissue is taken from the placenta and studied to detect the presence of the specific genetic mutation that has caused LAD I, LAD II or LAD III in that family. LAD II can also be detected before birth by identifying the characteristic blood type (Bombay blood phenotype) associated with the disorder. This is possible at approximately 20 weeks gestation.
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Therapies of Leukocyte Adhesion Deficiency Syndromes
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Treatment
The treatment of LAD syndromes are directed toward the specific symptoms that are apparent in each individual. The main aspect of treatment is antibiotic therapy to treat the repeated, characteristic infections associated with the LAD syndrome disorders. Prompt antibiotic therapy is essential during acute infectious episodes. Individuals with moderate or mild forms of LAD I or LAD II usually respond to conservative therapy and prompt treatment for acute episodes. Preventive (prophylactic) antibiotic therapy may be necessary for some individuals with more serious forms of LAD I.In the absence of tissue neutrophils in patients with LAD I, inhibition of the IL-23/IL-17 axis is deficient, resulting in an unregulated hyperinflammatory response, which leads to chronic inflammation. In patients with LAD I, this process is particularly important in the gingivae but may also be involved in poorly healing cutaneous wounds that often affect these patients. A case report described in vivo beneficial effects of ustekinumab, a monoclonal antibody that binds the p40 subunit shared by IL-12 and IL-23, in a patient with LAD I, with dramatic improvement of periodontitis and of sacral wound.In some cases, white blood cell (granulocyte) transfusions may be required to treat life-threatening infectious complications. Because of the possibility of adverse side effects, white blood cell transfusions are rarely used and only in severe cases when all other therapeutic options have failed. Blood transfusions are required for individuals with LAD III who experience severe bleeding episodes.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Leukocyte Adhesion Deficiency Syndromes. Treatment
The treatment of LAD syndromes are directed toward the specific symptoms that are apparent in each individual. The main aspect of treatment is antibiotic therapy to treat the repeated, characteristic infections associated with the LAD syndrome disorders. Prompt antibiotic therapy is essential during acute infectious episodes. Individuals with moderate or mild forms of LAD I or LAD II usually respond to conservative therapy and prompt treatment for acute episodes. Preventive (prophylactic) antibiotic therapy may be necessary for some individuals with more serious forms of LAD I.In the absence of tissue neutrophils in patients with LAD I, inhibition of the IL-23/IL-17 axis is deficient, resulting in an unregulated hyperinflammatory response, which leads to chronic inflammation. In patients with LAD I, this process is particularly important in the gingivae but may also be involved in poorly healing cutaneous wounds that often affect these patients. A case report described in vivo beneficial effects of ustekinumab, a monoclonal antibody that binds the p40 subunit shared by IL-12 and IL-23, in a patient with LAD I, with dramatic improvement of periodontitis and of sacral wound.In some cases, white blood cell (granulocyte) transfusions may be required to treat life-threatening infectious complications. Because of the possibility of adverse side effects, white blood cell transfusions are rarely used and only in severe cases when all other therapeutic options have failed. Blood transfusions are required for individuals with LAD III who experience severe bleeding episodes.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Overview of Leukodystrophy
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Leukodystrophies are a group of rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and often the peripheral nerves. Each type of leukodystrophy is caused by a specific gene abnormality that leads to abnormal development or destruction of the white matter (myelin sheath) of the brain. The myelin sheath is the protective covering of the nerve and nerves can't function normally without it. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems.
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Overview of Leukodystrophy. Leukodystrophies are a group of rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and often the peripheral nerves. Each type of leukodystrophy is caused by a specific gene abnormality that leads to abnormal development or destruction of the white matter (myelin sheath) of the brain. The myelin sheath is the protective covering of the nerve and nerves can't function normally without it. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems.
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Symptoms of Leukodystrophy
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Symptoms of some types of leukodystrophy begin shortly after birth, but others develop later in childhood or even in adulthood. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems. Leukodystrophy can cause problems with movement, vision, hearing, balance, ability to eat, memory, behavior, and thought. Leukodystrophies are progressive diseases meaning that the symptoms of the disease tend to get worse over time. Some inherited leukoencephalopathies have stable white matter abnormalities.Magnetic resonance imaging (MRI) has markedly increased the awareness of hereditary white matter diseases associated with the formation of myelin and hypomyelination, in addition to the previously described classic leukodystrophies. New disease entities based on MRI and clinical patterns have been defined through the committed collaboration of neurologists in medical centers around the world. While the following list includes many disorders that have recently been described, it is not complete as there are new leukodystrophies identified each year. With the advances in whole genome sequencing, there will be many more new genetic disorders found including those that affect the white matter of the brain.For more information on the following disorders, search the Rare Disease Database.Adult-onset autosomal dominant leukodystrophy (ADLD)
Adult-onset autosomal dominant leukodystrophy results from tandem duplication of the LMNB1 gene, which encodes the nuclear lamina protein lamin B1. Symptoms begin in the fourth to fifth decade with autonomic dysfunction including bowel and bladder dysfunction and orthostatic hypotension with lightheadedness. This is followed by slowly progressive motor and balance difficulties. The MRI of the brain shows extensive white matter involvement with relative sparing of the periventricular white matter. The spinal cord develops atrophy which may precede the motor difficulties.Adult polyglucosan body disease (APBD)
Adult polyglucosan body disease (APBD) is a rare, genetic disorder characterized by a deficiency of glycogen-branching enzyme, resulting in the accumulation of polyglucosan bodies in muscle, nerve and various other tissues of the body. Polyglucosan bodies are composed of large, complex, sugar-based molecules. APBD may be characterized by dysfunction of the central and peripheral nervous systems. In individuals with APBD, associated symptoms and findings may include sensory loss in the legs; progressive muscle weakness of the arms and legs; walking (gait) disturbances; progressive urinary difficulties; occasionally mild cognitive impairment or dementia; deficiencies in the autonomic nervous system; and/or other abnormalities. APBD is caused by mutations in the glycogen branching enzyme gene (GBE1) and is inherited in an autosomal recessive pattern.Aicardi-Goutieres syndrome
Aicardi-Goutieres syndrome is an autosomal recessive condition, presenting with an early encephalopathy followed by stabilization of neurologic symptoms. At least six different genes have been described. Neuroimaging reveals leukoencephalopathy with calcifications and cerebral atrophy. Cerebrospinal fluid analysis reveals chronic lymphocytosis (elevated white blood cell count), elevated INF-a, and neopterin.Alexander disease
Alexander disease is a rare, progressive, leukodystrophy that usually becomes apparent during infancy or early childhood but juvenile and adult onset forms have also been reported. Alexander disease is characterized by degenerative changes of the white matter of the brain caused by a lack of normal amounts of myelin. The disorder is also associated with the formation of abnormal, fibrous deposits known as “Rosenthal fibers” in the astrocytic processes around small blood vessels and astrocytic cell bodies in certain regions of the brain and spinal cord. The disease is caused by a dominant gain of function mutation in the glial fibrillary acidic protein (GFAP) (Chromosome 17q21). Treatment for Alexander’s disease is currently symptomatic consisting of anticonvulsants for seizures, orthopedic and pharmacologic management of spasticity, and nutritional support. Strategies for future treatment include decreasing the expression of GFAP.CADASIL
CADASIL is a rare genetic disorder with dominant inheritance caused by a mutation in the NOTCH3 receptor gene. This condition presents with migraine headaches and multiple strokes in adults, even young adults, often without cardiovascular risk factors. CADASIL often progresses to cause cognitive impairment and dementia. The symptoms of CADASIL result from damage of various small blood vessels, especially those within the brain. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. CADASIL is an acronym that stands for:(C)erebral – relating to the brain
(A)utosomal (D)ominant – a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder
(A)rteriopathy – disease of the small arteries (blood vessels that carry blood away from the heart)
(S)ubcortical – relating to a specific area of the deep brain that is involved in higher functioning (e.g., voluntary movements, reasoning, memory)
(I)nfarcts – tissue loss in the brain caused by lack of oxygen to the brain, which occurs when blood flow in the small arteries is blocked or abnormal
(L)eukoencephalopathy – destruction of the myelin, that covers and protects nerve fibers in the central nervous systemCanavan disease
Canavan disease is a rare inherited neurological disorder characterized by spongy degeneration of the brain and spinal cord (central nervous system). Physical symptoms that appear in early infancy may include progressive mental decline accompanied by the loss of muscle tone, poor head control, an abnormally large head (macrocephaly), and/ or irritability. Physical symptoms appear in early infancy and usually progress rapidly. Canavan disease is caused by an abnormality in the ASPA gene (Chromosome 17p13-ter0) that leads to a deficiency of the enzyme aspartoacylase. Canavan disease is inherited as an autosomal recessive genetic disorder. There are two common mutations among the Ashkenazi Jewish individuals that account for over 97% of the alleles in Jewish patients with Canavan disease.CARASIL
CARASIL is rare autosomal recessive disorder that is caused by mutations in cerebral small-vessel disease protein HTRA1 that controls the amount of TGF-B1 via cleavage of proTGF-B1b. Individuals with CARASIL are at risk of developing multiple strokes, even if they do not have cardiovascular risk factors. The symptoms of CARASIL result from damage to various small blood vessels, especially those within the brain. Individuals with CARASIL may develop a variety of symptoms relating to white matter involvement or leukoaraiosis (changes in deep white matter in the brain, which are observed on MRI). Such symptoms include an increasing muscle tone (spasticity), pyramidal signs, and pseudo bulbar palsy beginning between 20 and 30 years of age. Pseudo bulbar palsy is a group of neurologic symptoms including difficulties with chewing, swallowing and speech. Eventually, cognitive impairment and dementia may result. About half of cases have a stroke-like episode. The age of onset is 20 to 50 years old. CARASIL is an acronym that stands for:(C)erebral – relating to the brain or the cerebellum, which is the part of the brain that controls balance and muscular coordination
(A)utosomal (R)ecessive – a form of inheritance in which two copies (one from each parent) of an abnormal gene is necessary for the development of a disorder
(A)rteriopathy – disease of the small arteries (blood vessels that carry blood away from the heart)
(S)ubcortical – relating to a specific area of the deep brain that is involved in higher functioning (e.g., voluntary movements, reasoning, memory)
(I)nfarcts – tissue loss in the cerebellum caused by lack of oxygen to the brain, which occurs when blood flow in the small arteries is blocked or abnormal
(L)eukoencephalopathy – destruction of the myelin, an oily substance that covers and protects nerve fibers in the central nervous systemCerebrotendinous xanthomatosis
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive genetic disorder due to mutations in the sterol 27-hydroxylase gene (CYP27A1), resulting in a deficiency of the mitochondrial enzyme sterol 27-hydroxylase. The lack of this enzyme prevents cholesterol from being converted into a bile acid called chenodexoycholic acid. Lipid rich deposits containing cholestanol and cholesterol accumulate in the nerve cells and membranes, and cause damage to the brain, spinal cord, tendons, lens of the eye and arteries. Affected individuals experience cataracts during childhood and benign, fatty tumors (xanthomas) of the tendons during adolescence. The disorder leads to progressive neurologic problems in adulthood such as paralysis, ataxia and dementia. Coronary heart disease is common. More than 300 patients with CTX have been reported to date worldwide and about 50 different mutations identified in the CYP27A1 gene. Almost all mutations lead to the absent or inactive form of the sterol 27-hydroxylase. Dietary therapy with the bile acid, chenodeoxycholic acid, does correct many of the symptoms of CTX; however, early diagnosis of the disorder with early therapy leads to a better clinical outcome. The activity of cholesterol 7 alpha-hydroxylase, the rate limiting enzyme in bile acid synthesis, is normalized by this diet therapy and there is a reduction in the development of xanthomas.Childhood ataxia with cerebral hypomyelination
Childhood ataxia with cerebral hypomyelination (CACH), also known as vanishing white matter disease (VWMD), is an autosomal recessive leukodystrophy that is characterized by progressive deterioration in motor function and speech during the first five years of life. Clinical symptoms typically begin in the first few years of life, following a normal to mildly delayed early development. Common presenting symptoms include ataxia and seizures. The course is chronic and progressive with episodic decline following fever, head trauma, or periods of fright. Patients usually survive only a few years past the clinical onset, though the course is variable even among patients with mutations in the same eIF2B subunit. In the rare reports of adult-onset VWMD, the typical presentation consists of cognitive deterioration, pseudo bulbar palsy and progressive spastic paraparesis. An important association between VWMD and ovarian failure has been described, termed ‘ovarioleukodystrophy’. VWMD may be one of the more common inherited leukoencephalopathies, though its exact incidence is not yet known.VWMD is caused by mutations in one of the 5 subunits of eukaryotic initiation factor 2B (eIF2B). eIF2B is a highly conserved, ubiquitously expressed protein that plays an essential role in the initiation of protein synthesis by catalyzing the GDP-GTP exchange on eIF2 to enable binding of methionyl-transfer-RNA to the ribosome. Despite the essential role of eIF2B in all cells, its defect curiously causes selective damage of white matter and in some cases damage to the ovaries alone. The ability of glia to regulate eIF2 activity may represent a critical protective mechanism in response to stress conditions.Fabry disease
Fabry disease is a progressive X-linked lysosomal disorder due to a deficiency of the enzyme alpha-galactosidase A, leading to an accumulation of glycosphingolipids, mainly globotriaosylceramide GL-3 in lysosomes. This accumulation triggers tissue ischemia and fibrosis. The classic form of the disease presenting in males with no detectable enzyme activity, is characterized by angiokeratomas, acroparesthesia, hyperhidrosis, corneal opacity in childhood or adolescence and progressive vascular disease of the heart, kidneys, and central nervous system. MRI findings include white matter abnormalities and vertebrobasilar stroke. In contrast, patients with mild forms of Fabry disease (female carriers and males with residual alpha-galactosidase activity) may remain asymptomatic until late adulthood. The incidence of Fabry disease is estimated to be 1/100,000; however, with the advent of newborn screening the true incidence will be determined. Recently enzyme replacement therapy and pharmacological chaperone therapy have been introduced to lower the GL-3 accumulation in the lysosome.Fucosidosis
Fucosidosis is a rare autosomal recessive disorder characterized by deficiency of the lysosomal enzyme alpha-L-fucosidase, which is required to break down (metabolize) certain complex compounds (e.g., fucose-containing glycolipids or fucose-containing glycoproteins). Fucose is a type of the sugar required by the body to perform certain functions (essential sugar). The inability to breakdown fucose-containing compounds results in their accumulation in various tissues in the body. Fucosidosis results in progressive neurological deterioration, skin abnormalities, delayed growth, skeletal disease and coarsening of facial features. The symptoms and severity of fucosidosis are highly variable and the disorder represents a disease spectrum in which individuals with mild cases have been known to live into the third or fourth decades. Individuals with severe cases of fucosidosis can develop life-threatening complications early in childhood. Hypomyelination is present on the MRI scans.The disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain fats and carbohydrates. Low levels or inactivity of the alpha-L-fucosidase enzyme leads to the abnormal accumulation of fucose-containing compounds in the tissues of individuals with fucosidosis.GM1 gangliosidosis
GM1 gangliosidosis is an autosomal recessive disorder due to deficiency of the lysosomal enzyme ß-galactosidase associated with mutations in the GLB1 gene. More than 100 mutations have been described. ß-galactosidase hydrolyses the ß-galactosyl residue from GM1 ganglioside, glycoproteins, and glycosaminoglycans. Deficiency of ß-galactosidase results in lysosomal storage of these substances, particularly in the central nervous system (CNS). Three types of GM1 gangliosidosis have been described. Type 1 or infantile GM1 gangliosidosis has its onset before 6 months of age with rapidly progressive hypotonia (low body tone) and CNS deterioration resulting in death by 1 to 2 years of age. Type II or late-infantile/ juvenile GM1 gangliosidosis presents with delay in cognitive and motor development between 7 months and 3 years of age with slow progression. Adult-onset GM1 gangliosidosis presents between 3 to 30 years of age with a progressive extrapyramidal disorder. MRI findings include delayed myelination, diffuse white matter abnormalities and abnormal signal in the basal ganglia.L-2-hydroxyglutaric aciduria
L-2-hydroxyglutaric aciduria is a rare autosomal recessive disorder. Mutations in both copies of the L2HDGH gene result in deficiency of L-2-hydroxyglutarate dehydrogenase activity. L-2 hydroxyglutarate dehydrogenase is an FAD-linked mitochondrial enzyme that converts L-2 hydroxyglutarate to a-ketoglutarate. Biochemically, L-2-hydroxyglutaric aciduria presents with significantly elevated levels of L-2-hydroxyglutaric acid in the urine and CSF. Plasma amino acids reveal elevated lysine. Clinically, L-2 hydroxyglutaric aciduria presents with variable degrees of psychomotor and speech delay followed by a slowly progressive neurodegenerative disorder with cognitive decline. The MRI demonstrate a complex but characteristic pattern of abnormal signal intensity in the subcortical white matter bilaterally with frontal predominance and involvement of the globus pallidus, caudate and putamen bilaterally as well as the dentate nucleusAn increased risk of brain tumors has been described.Krabbe disease
Krabbe disease also known as globoid cell leukodystrophy, is an autosomal recessive lipid storage disorder caused by a deficiency of the lysosomal enzyme galactocerebrosidase (GALC), which is necessary for the breakdown (metabolism) of the sphingolipids galactosylceramide and psychosine (galactosyl-sphingosine). Failure to break down these sphingolipids results in degeneration of the myelin sheath surrounding nerves in the brain (demyelination). Characteristic globoid cells appear in affected areas of the brain. This metabolic disorder is characterized by progressive neurological dysfunction with irritability, developmental regression, abnormal body tone, seizures and peripheral neuropathy. The MRI may appear normal early in the disease course but eventually demonstrates diffuse white matter abnormalities. More than 75 mutations have been described in the GALC gene. There is limited correlation between genotype and phenotype, with the exception of homozygosity for the common 30kb deletion being predictive of early-infantile Krabbe disease and having at least one G809A allele being compatible with juvenile or adult onset. Otherwise, the genotype–phenotype correlation is poor, making prediction of the early-infantile phenotype at birth difficult. The incidence of Krabbe disease has been estimated at 1 in 100,000, with 85 to 90% of patients having the early-infantile form, although recent newborn screening results suggest that a higher proportion of patients may have later onset forms. Early hematopoietic stem cell transplantation attenuates the clinical course of infantile Krabbe disease and prolongs survival but is not curative.Megalencephalic leukoencephalopathy with subcortical cysts
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive condition which initially presents with macrocephaly (enlarged head size). Mild motor delay is followed by gradual motor deterioration with ataxia and spasticity. Cognitive abilities are relatively spared but seizures may occur in this classical form. Recessive MLC1 mutations are observed in 80% of patients with MLC. Other patients with the classical, deteriorating phenotype have two mutations in the HEPACAM gene. An improving phenotype has been described in patients with only one mutation in HEPACAM. Most parents with a single mutation had macrocephaly, indicating dominant inheritance. In some families with dominant HEPACAM mutations, the clinical picture and magnetic resonance imaging normalized, indicating that HEPACAM mutations can cause benign familial macrocephaly. In other families with dominant HEPACAM mutations, patients had macrocephaly and intellectual disability with or without autism. Diffuse white matter abnormalities on MRI are accompanied by anterior temporal cysts.Metachromatic leukodystrophy
Metachromatic leukodystrophy is an autosomal recessive lysosomal storage disease caused by the deficiency of arylsulphatase A (ASA). This leads to the accumulation of a fatty substance known as sulfatide, sphingolipid, in the brain and other areas of the body (i.e., liver, gall bladder, kidneys, and/or spleen). Myelin is lost from areas of the central nervous system and peripheral nerves due to the buildup of sulfatide. Symptoms of metachromatic leukodystrophy may include seizures, personality changes, spasticity, progressive dementia, painful paresthesias, motor disturbances progressing to paralysis, and/or visual impairment leading to blindness. Infantile, juvenile, and adult onset forms of metachromatic leukodystrophy have been distinguished. There is evidence for genotype-phenotype correlation. Patients with 2 mutations that do not allow expression of the ASA enzyme suffer from the late infantile form whereas the juvenile patients have more residual enzyme activity. ASA-deficient mice have been produced which have led to a better understanding of the disease process and to various therapeutic trials involving enzyme replacement therapy, haematopoietic stem-cell transplant and gene therapy.Multiple sulfatase deficiency
Multiple sulfatase deficiency (MSD) is a very rare leukodystrophy in which all of the known sulfatase enzymes (thought to be seven in number) are deficient or inoperative due to mutations in the SUMF1 gene. Major symptoms include mildly coarsened facial features, deafness, and an enlarged liver and spleen (hepatosplenomegaly). Abnormalities of the skeleton may occur, such as curvature of the spine (lumbar kyphosis) and the breast bone. The skin is usually dry and scaly (ichthyosis). Before symptoms are noticeable, children with this disorder usually develop more slowly than normal. They may not learn to walk or speak as quickly as other children.Similar to metachromatic leukodystrophy, multiple sulfatase deficiency patients exhibit neurodegenerative disease in early childhood due to central nervous system (CNS) and peripheral demyelination with loss of sensory and motor functions. They also develop intellectual disability, hepatosplenomegaly, coarse facies, and corneal clouding as seen in patients with mucopolysaccharidoses. Ichthyosis and skeletal changes reflect enzyme deficiencies of steroid sulfatase (X-linked ichthyosis) and arylsulfatase E (chondrodysplasia punctata), respectively. The unique combination of neurodegeneration, coarse facial features, hepatosplenomegaly, and ichthyosis is not seen in other neuro-ichthyotic disorders. However, the sequential appearance of these clinical signs often delays the diagnosis of MSD.Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease, also known as X-linked spastic paraplegia, is a rare inherited disorder affecting the central nervous system that is associated with a lack of myelin sheath. Many areas of the central nervous system may be affected, including the deep portions of the cerebrum (subcortical), cerebellum, and/or brain stem. Symptoms may include the impaired ability to coordinate movement (ataxia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs, delays in reaching developmental milestones, loss of motor abilities, and the progressive deterioration of intellectual function. The symptoms of Pelizaeus-Merzbacher disease (PMD) are usually slowly progressive. Several forms of the disorder have been identified, including classical X-linked PMD; acute infantile (or connatal) PMD; and adult-onset (or late-onset) PMD. Various types of mutations of the X-linked proteolipid protein 1 gene (PLP1) that include copy number changes, point mutations, and insertions or deletions of a few bases lead to a clinical spectrum from the most severe connatal PMD, to the least severe spastic paraplegia 2 (SPG2). The most common form of PMD is caused by a duplication of the PLP1 gene and affects males. Signs of PMD include nystagmus, hypotonia, tremors, titubation, ataxia, spasticity, athetotic movements and cognitive impairment; the major findings in SPG2 are leg weakness and spasticity. Supportive therapy for patients with PMD/SPG2 includes medications for seizures and spasticity; physical therapy, exercise, and orthotics for spasticity management; surgery for contractures and scoliosis; gastrostomy for severe dysphagia; proper wheelchair seating, physical therapy, and orthotics to prevent or ameliorate the effects of scoliosis; special education; and assistive communication devices.An autosomal recessive condition clinically resembling classical PMD, PMD-like disease, has been described due to mutations in gap junction protein (GJA12). This condition affects both males and females.Pol III-Related Leukodystrophies
The Pol III-related leukodystrophies comprise a group of 5 overlapping clinically defined hypomyelinating leukodystrophies including: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH);Leukodystrophy with oligodontia (LO); and Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). These conditions present with varying combinations of motor dysfunction, abnormal teeth and hypogonadotropic hypogonadism. The MRI scan of the brain demonstrates hypomyelination. The condition is associated with autosomal recessive mutations in POLR3A or POLR3B.Refsum disease
Refsum disease, also called hereditary sensory motor neuropathy type IV, is an autosomal recessive leukodystrophy in which the myelin sheath fails to grow. The disorder is caused by the accumulation of a methyl branched chain fatty acid (phytanic acid) in blood plasma and tissues due to mutations in the PHYH gene that encodes the peroxisomal enzyme phytanoyl-CoA hydroxylase that is responsible for the a-oxidation of phytanic acid. 90% of patients with Refsum disease have a mutation in the PHYH gene; whereas the remaining 10% have a mutation in the peroxisomal gene, Pex7, which is necessary for import of phytanoyl-CoA hydroxylase into peroxisomes. Refsum disease is characterized by progressive loss of vision (retinitis pigmentosa); degenerative nerve disease (peripheral neuropathy); failure of muscle coordination (ataxia); and dry, rough, scaly skin (ichthyosis). Treatment with a diet low in phytanic acid and avoidance of foods such as cold water fish, dairy and ruminant meats that contain phytanic acid can be beneficial. Plasmapheresis and the intestinal lipase inhibitor, Orlistat have shown some efficacy in lowering phytanic acid levels. However these therapies, while successful at diminishing the neurological symptoms do not prevent the slow progression of retinitis pigmentosa.Salla disease
Salla disease is a rare autosomal recessive disorder due to deficiency of the sialic acid transporter, SLC17A5. Free sialic acid (N-acetylneuraminic acid) accumulates in lysosomes in various tissues. The severe form, infantile free sialic acid storage disorder, results in early death. Salla’s disease, which is more common in patients of Finnish descent, has wide clinical variability. Most children present between 3 and 9 months of age with hypotonia, ataxia, delayed motor milestones, and transient nystagmus. Cognitive delay and slow motor decline occurs after the second to third decade. Peripheral neuropathy may be present and contribute to motor disability. MRI findings are consistent with hypomyelination with minimal or extremely slow myelination. Myelin is present in the internal capsule and is usually normal in the cerebellum. The corpus callosum is usually thin. Treatment for Salla’s disease is supportive.Sjögren-Larsson syndrome
Sjögren-Larsson syndrome (SLS) is caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase is located on chromosome 17p11.2. More than 70 different mutations in the ALDH3A2 gene have been identified in SLS patients originating from about 120 different families. Fatty aldehyde dehydrogenase is necessary for the oxidation of long-chain aldehydes and alcohols to fatty acids. Deficiency of this enzyme leads to accumulation of these lipids leading to increased inflammatory lipids, the leukotrienes, in skin and brain, which are thought to be directly responsible for the symptoms of ichthyosis and delay in myelination. About 70% of SLS patients are born preterm most likely due to the fetal excretion of abnormal lipids and leukotrienes causing inflammation and early labor. During early childhood (1–2 years of age) intellectual and motor disabilities gradually become clear, however, the typical MRI and H-MRS abnormalities, as well as crystalline maculopathy, may be absent, and normal radiologic and ocular findings do not exclude SLS at this stage. Later on in childhood (from 3 years of age), the full-blown phenotype of SLS with the classical triad of ichthyosis, spasticity, and intellectual disability is present with the typical findings of ophthalmological and MRI/H-MRS studies. Therapies consist of preventing skin lesions through application of special creams and urea-containing emollients and physical therapy and bracing to diminish contractures. Therapies to reduce the levels of leukotrienes, to prevent the skin lesions and improve neurological functioning are being studied.X-linked adrenoleukodystrophy
X-linked adrenoleukodystrophy (ALD) is the most common leukodystrophy and affects the myelin or white matter of the brain and the spinal cord as well as the adrenal cortex. The gene for ALD, the ABCD1 gene, is located at Xq28 and encodes a peroxisomal protein belonging to the ATPase Binding Cassette proteins. There have been more than 1000 mutations reported in the ABCD1 gene (www.x-ald.nl). ALD is a progressive disease characterized by an accumulation of very long chain fatty acids, mainly of 26 carbons in chain length. There are several phenotypes of ALD, each distinguished by the age of onset and by the features that are present. All phenotypes can occur in the same kindred with 31-35% of affected males having the demyelinating childhood cerebral form (CCER) with typical onset between 4 and 8 yrs. Boys develop normally until the onset of cognitive decline and progressive neurologic deficits which lead to a vegetative state, blindness, seizures and death often within 3 yrs. Forty to 46% of males with ALD present in early adulthood with slowly progressive paraparesis (weakness and spasticity), sensory, and sphincter disturbances involving spinal cord long tracts. This form is called adrenomyeloneuropathy (AMN). At least 30% of men with AMN develop cerebral involvement that is similar to CCER. Fifty per cent of heterozygous females (carriers) develop overt neurologic disturbances resembling AMN, with a mean age of onset of 37 yrs. The minimum frequency of hemizygotes (i.e., affected males) identified in the United States is estimated at 1:21,000 and that of hemizygotes plus heterozygotes (i.e., carrier females) 1:16,800.Untreated adrenal insufficiency can be fatal and occurs independent of neurological symptoms. Earlier onset of CCER correlates with more severe, rapidly progressive clinical manifestations. Boys with parieto-occipital lobe disease demonstrate visual and/or auditory processing abnormalities, impaired communication skills and gait disturbances prior to death. Boys with frontal lobe involvement have signs/symptoms similar to ADHD and are often misdiagnosed prior to death. The extent of demyelination can be quantitated using the MRI severity score of Loes.ALD in boys can be diagnosed by analysis of the very long chain fatty acids in plasma and if positive, mutation analysis of the ABCD1 gene is recommended. For females at risk of ALD, the most accurate test is targeted analysis of the family mutation in the ABCD1 gene as the plasma very long chain fatty acid test for females has a 20% false negative rate due to lyonization (selective X-inactivation) of the X-chromosome. It is important to screen all at-risk relatives for ALD as the males with ALD are at risk for Addison disease which is treatable with life-saving hormone therapy. Dietary therapy with Lorenzo’s oil if started early before MRI abnormalities occur and if plasma levels of very long chain fatty acids are normalized, has shown to statistically lower the development of CCER. Over one third of ALD boys will develop CCER thus ALD boys who are diagnosed before neurological symptoms occur should be followed by a pediatric neurologist and have MRI every 6 months. At first signs of progressive white matter abnormalities on MRI, bone marrow transplantation, or hematopoetic cell transplantation (HCT), is recommended as the only effective long-term treatment for CCER; however, to achieve optimal survival and clinical outcomes, HCT must occur prior to manifestations of symptoms. Gene therapy experimental treatment has been shown to be safe and efficacious.With the development of a newborn screening test for ALD all boys with ALD will be diagnosed at an age before Addison disease and brain dysfunction occur. Thus life-saving therapies can be implemented early and other at risk relatives identified.Zellweger syndrome spectrum disorders
Zellweger syndrome spectrum disorders, also known as peroxisomal biogenesis disorders (PBDs), are characterized by a deficiency or absence of peroxisomes in the cells of the liver, kidneys, and brain. Peroxisomes are very small, membrane-bound structures within the cytoplasm of cells that function as part of the body’s waste disposal system. In the absence of the enzymes normally found in peroxisomes, waste products, especially very long chain fatty acids (VLCFA), accumulate in the cells of the affected organ. The accumulation of these waste products has profound effects on the development of the fetus. PBDs are inherited as autosomal recessive disorders and have two clinically distinct subtypes: the Zellweger syndrome spectrum (ZSS) disorders and rhizomelic chondrodysplasia punctata (RCDP) type 1. PBDs are caused by defects in any of at least 14 different PEX genes, which encode proteins involved in peroxisome assembly and proliferation. There is genetic heterogeneity among PBDs and this is present in all defective PEX genes. The PBDs with the mildest phenotype are known by the clinical names, neonatal adrenoleukodystrophy and infantile Refsum’s disease. A range of symptoms are seen including developmental delay, sensorineural hearing loss, visual abnormalities, adrenal insufficiency and liver dysfunction. MRI scans may show developmental abnormalities of the brain and progressive white matter changes may develop. Diagnosis of PBDs is made by finding an increase in the plasma very long chain fatty acids (VLCFA) and the branched chain fatty acids, phytanic and pristanic. Additional biochemical laboratory tests are the measurement of red blood cell plasmalogens.
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Symptoms of Leukodystrophy. Symptoms of some types of leukodystrophy begin shortly after birth, but others develop later in childhood or even in adulthood. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems. Leukodystrophy can cause problems with movement, vision, hearing, balance, ability to eat, memory, behavior, and thought. Leukodystrophies are progressive diseases meaning that the symptoms of the disease tend to get worse over time. Some inherited leukoencephalopathies have stable white matter abnormalities.Magnetic resonance imaging (MRI) has markedly increased the awareness of hereditary white matter diseases associated with the formation of myelin and hypomyelination, in addition to the previously described classic leukodystrophies. New disease entities based on MRI and clinical patterns have been defined through the committed collaboration of neurologists in medical centers around the world. While the following list includes many disorders that have recently been described, it is not complete as there are new leukodystrophies identified each year. With the advances in whole genome sequencing, there will be many more new genetic disorders found including those that affect the white matter of the brain.For more information on the following disorders, search the Rare Disease Database.Adult-onset autosomal dominant leukodystrophy (ADLD)
Adult-onset autosomal dominant leukodystrophy results from tandem duplication of the LMNB1 gene, which encodes the nuclear lamina protein lamin B1. Symptoms begin in the fourth to fifth decade with autonomic dysfunction including bowel and bladder dysfunction and orthostatic hypotension with lightheadedness. This is followed by slowly progressive motor and balance difficulties. The MRI of the brain shows extensive white matter involvement with relative sparing of the periventricular white matter. The spinal cord develops atrophy which may precede the motor difficulties.Adult polyglucosan body disease (APBD)
Adult polyglucosan body disease (APBD) is a rare, genetic disorder characterized by a deficiency of glycogen-branching enzyme, resulting in the accumulation of polyglucosan bodies in muscle, nerve and various other tissues of the body. Polyglucosan bodies are composed of large, complex, sugar-based molecules. APBD may be characterized by dysfunction of the central and peripheral nervous systems. In individuals with APBD, associated symptoms and findings may include sensory loss in the legs; progressive muscle weakness of the arms and legs; walking (gait) disturbances; progressive urinary difficulties; occasionally mild cognitive impairment or dementia; deficiencies in the autonomic nervous system; and/or other abnormalities. APBD is caused by mutations in the glycogen branching enzyme gene (GBE1) and is inherited in an autosomal recessive pattern.Aicardi-Goutieres syndrome
Aicardi-Goutieres syndrome is an autosomal recessive condition, presenting with an early encephalopathy followed by stabilization of neurologic symptoms. At least six different genes have been described. Neuroimaging reveals leukoencephalopathy with calcifications and cerebral atrophy. Cerebrospinal fluid analysis reveals chronic lymphocytosis (elevated white blood cell count), elevated INF-a, and neopterin.Alexander disease
Alexander disease is a rare, progressive, leukodystrophy that usually becomes apparent during infancy or early childhood but juvenile and adult onset forms have also been reported. Alexander disease is characterized by degenerative changes of the white matter of the brain caused by a lack of normal amounts of myelin. The disorder is also associated with the formation of abnormal, fibrous deposits known as “Rosenthal fibers” in the astrocytic processes around small blood vessels and astrocytic cell bodies in certain regions of the brain and spinal cord. The disease is caused by a dominant gain of function mutation in the glial fibrillary acidic protein (GFAP) (Chromosome 17q21). Treatment for Alexander’s disease is currently symptomatic consisting of anticonvulsants for seizures, orthopedic and pharmacologic management of spasticity, and nutritional support. Strategies for future treatment include decreasing the expression of GFAP.CADASIL
CADASIL is a rare genetic disorder with dominant inheritance caused by a mutation in the NOTCH3 receptor gene. This condition presents with migraine headaches and multiple strokes in adults, even young adults, often without cardiovascular risk factors. CADASIL often progresses to cause cognitive impairment and dementia. The symptoms of CADASIL result from damage of various small blood vessels, especially those within the brain. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. CADASIL is an acronym that stands for:(C)erebral – relating to the brain
(A)utosomal (D)ominant – a form of inheritance in which one copy of an abnormal gene is necessary for the development of a disorder
(A)rteriopathy – disease of the small arteries (blood vessels that carry blood away from the heart)
(S)ubcortical – relating to a specific area of the deep brain that is involved in higher functioning (e.g., voluntary movements, reasoning, memory)
(I)nfarcts – tissue loss in the brain caused by lack of oxygen to the brain, which occurs when blood flow in the small arteries is blocked or abnormal
(L)eukoencephalopathy – destruction of the myelin, that covers and protects nerve fibers in the central nervous systemCanavan disease
Canavan disease is a rare inherited neurological disorder characterized by spongy degeneration of the brain and spinal cord (central nervous system). Physical symptoms that appear in early infancy may include progressive mental decline accompanied by the loss of muscle tone, poor head control, an abnormally large head (macrocephaly), and/ or irritability. Physical symptoms appear in early infancy and usually progress rapidly. Canavan disease is caused by an abnormality in the ASPA gene (Chromosome 17p13-ter0) that leads to a deficiency of the enzyme aspartoacylase. Canavan disease is inherited as an autosomal recessive genetic disorder. There are two common mutations among the Ashkenazi Jewish individuals that account for over 97% of the alleles in Jewish patients with Canavan disease.CARASIL
CARASIL is rare autosomal recessive disorder that is caused by mutations in cerebral small-vessel disease protein HTRA1 that controls the amount of TGF-B1 via cleavage of proTGF-B1b. Individuals with CARASIL are at risk of developing multiple strokes, even if they do not have cardiovascular risk factors. The symptoms of CARASIL result from damage to various small blood vessels, especially those within the brain. Individuals with CARASIL may develop a variety of symptoms relating to white matter involvement or leukoaraiosis (changes in deep white matter in the brain, which are observed on MRI). Such symptoms include an increasing muscle tone (spasticity), pyramidal signs, and pseudo bulbar palsy beginning between 20 and 30 years of age. Pseudo bulbar palsy is a group of neurologic symptoms including difficulties with chewing, swallowing and speech. Eventually, cognitive impairment and dementia may result. About half of cases have a stroke-like episode. The age of onset is 20 to 50 years old. CARASIL is an acronym that stands for:(C)erebral – relating to the brain or the cerebellum, which is the part of the brain that controls balance and muscular coordination
(A)utosomal (R)ecessive – a form of inheritance in which two copies (one from each parent) of an abnormal gene is necessary for the development of a disorder
(A)rteriopathy – disease of the small arteries (blood vessels that carry blood away from the heart)
(S)ubcortical – relating to a specific area of the deep brain that is involved in higher functioning (e.g., voluntary movements, reasoning, memory)
(I)nfarcts – tissue loss in the cerebellum caused by lack of oxygen to the brain, which occurs when blood flow in the small arteries is blocked or abnormal
(L)eukoencephalopathy – destruction of the myelin, an oily substance that covers and protects nerve fibers in the central nervous systemCerebrotendinous xanthomatosis
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive genetic disorder due to mutations in the sterol 27-hydroxylase gene (CYP27A1), resulting in a deficiency of the mitochondrial enzyme sterol 27-hydroxylase. The lack of this enzyme prevents cholesterol from being converted into a bile acid called chenodexoycholic acid. Lipid rich deposits containing cholestanol and cholesterol accumulate in the nerve cells and membranes, and cause damage to the brain, spinal cord, tendons, lens of the eye and arteries. Affected individuals experience cataracts during childhood and benign, fatty tumors (xanthomas) of the tendons during adolescence. The disorder leads to progressive neurologic problems in adulthood such as paralysis, ataxia and dementia. Coronary heart disease is common. More than 300 patients with CTX have been reported to date worldwide and about 50 different mutations identified in the CYP27A1 gene. Almost all mutations lead to the absent or inactive form of the sterol 27-hydroxylase. Dietary therapy with the bile acid, chenodeoxycholic acid, does correct many of the symptoms of CTX; however, early diagnosis of the disorder with early therapy leads to a better clinical outcome. The activity of cholesterol 7 alpha-hydroxylase, the rate limiting enzyme in bile acid synthesis, is normalized by this diet therapy and there is a reduction in the development of xanthomas.Childhood ataxia with cerebral hypomyelination
Childhood ataxia with cerebral hypomyelination (CACH), also known as vanishing white matter disease (VWMD), is an autosomal recessive leukodystrophy that is characterized by progressive deterioration in motor function and speech during the first five years of life. Clinical symptoms typically begin in the first few years of life, following a normal to mildly delayed early development. Common presenting symptoms include ataxia and seizures. The course is chronic and progressive with episodic decline following fever, head trauma, or periods of fright. Patients usually survive only a few years past the clinical onset, though the course is variable even among patients with mutations in the same eIF2B subunit. In the rare reports of adult-onset VWMD, the typical presentation consists of cognitive deterioration, pseudo bulbar palsy and progressive spastic paraparesis. An important association between VWMD and ovarian failure has been described, termed ‘ovarioleukodystrophy’. VWMD may be one of the more common inherited leukoencephalopathies, though its exact incidence is not yet known.VWMD is caused by mutations in one of the 5 subunits of eukaryotic initiation factor 2B (eIF2B). eIF2B is a highly conserved, ubiquitously expressed protein that plays an essential role in the initiation of protein synthesis by catalyzing the GDP-GTP exchange on eIF2 to enable binding of methionyl-transfer-RNA to the ribosome. Despite the essential role of eIF2B in all cells, its defect curiously causes selective damage of white matter and in some cases damage to the ovaries alone. The ability of glia to regulate eIF2 activity may represent a critical protective mechanism in response to stress conditions.Fabry disease
Fabry disease is a progressive X-linked lysosomal disorder due to a deficiency of the enzyme alpha-galactosidase A, leading to an accumulation of glycosphingolipids, mainly globotriaosylceramide GL-3 in lysosomes. This accumulation triggers tissue ischemia and fibrosis. The classic form of the disease presenting in males with no detectable enzyme activity, is characterized by angiokeratomas, acroparesthesia, hyperhidrosis, corneal opacity in childhood or adolescence and progressive vascular disease of the heart, kidneys, and central nervous system. MRI findings include white matter abnormalities and vertebrobasilar stroke. In contrast, patients with mild forms of Fabry disease (female carriers and males with residual alpha-galactosidase activity) may remain asymptomatic until late adulthood. The incidence of Fabry disease is estimated to be 1/100,000; however, with the advent of newborn screening the true incidence will be determined. Recently enzyme replacement therapy and pharmacological chaperone therapy have been introduced to lower the GL-3 accumulation in the lysosome.Fucosidosis
Fucosidosis is a rare autosomal recessive disorder characterized by deficiency of the lysosomal enzyme alpha-L-fucosidase, which is required to break down (metabolize) certain complex compounds (e.g., fucose-containing glycolipids or fucose-containing glycoproteins). Fucose is a type of the sugar required by the body to perform certain functions (essential sugar). The inability to breakdown fucose-containing compounds results in their accumulation in various tissues in the body. Fucosidosis results in progressive neurological deterioration, skin abnormalities, delayed growth, skeletal disease and coarsening of facial features. The symptoms and severity of fucosidosis are highly variable and the disorder represents a disease spectrum in which individuals with mild cases have been known to live into the third or fourth decades. Individuals with severe cases of fucosidosis can develop life-threatening complications early in childhood. Hypomyelination is present on the MRI scans.The disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes are particles bound in membranes within cells that function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular nutrients, such as certain fats and carbohydrates. Low levels or inactivity of the alpha-L-fucosidase enzyme leads to the abnormal accumulation of fucose-containing compounds in the tissues of individuals with fucosidosis.GM1 gangliosidosis
GM1 gangliosidosis is an autosomal recessive disorder due to deficiency of the lysosomal enzyme ß-galactosidase associated with mutations in the GLB1 gene. More than 100 mutations have been described. ß-galactosidase hydrolyses the ß-galactosyl residue from GM1 ganglioside, glycoproteins, and glycosaminoglycans. Deficiency of ß-galactosidase results in lysosomal storage of these substances, particularly in the central nervous system (CNS). Three types of GM1 gangliosidosis have been described. Type 1 or infantile GM1 gangliosidosis has its onset before 6 months of age with rapidly progressive hypotonia (low body tone) and CNS deterioration resulting in death by 1 to 2 years of age. Type II or late-infantile/ juvenile GM1 gangliosidosis presents with delay in cognitive and motor development between 7 months and 3 years of age with slow progression. Adult-onset GM1 gangliosidosis presents between 3 to 30 years of age with a progressive extrapyramidal disorder. MRI findings include delayed myelination, diffuse white matter abnormalities and abnormal signal in the basal ganglia.L-2-hydroxyglutaric aciduria
L-2-hydroxyglutaric aciduria is a rare autosomal recessive disorder. Mutations in both copies of the L2HDGH gene result in deficiency of L-2-hydroxyglutarate dehydrogenase activity. L-2 hydroxyglutarate dehydrogenase is an FAD-linked mitochondrial enzyme that converts L-2 hydroxyglutarate to a-ketoglutarate. Biochemically, L-2-hydroxyglutaric aciduria presents with significantly elevated levels of L-2-hydroxyglutaric acid in the urine and CSF. Plasma amino acids reveal elevated lysine. Clinically, L-2 hydroxyglutaric aciduria presents with variable degrees of psychomotor and speech delay followed by a slowly progressive neurodegenerative disorder with cognitive decline. The MRI demonstrate a complex but characteristic pattern of abnormal signal intensity in the subcortical white matter bilaterally with frontal predominance and involvement of the globus pallidus, caudate and putamen bilaterally as well as the dentate nucleusAn increased risk of brain tumors has been described.Krabbe disease
Krabbe disease also known as globoid cell leukodystrophy, is an autosomal recessive lipid storage disorder caused by a deficiency of the lysosomal enzyme galactocerebrosidase (GALC), which is necessary for the breakdown (metabolism) of the sphingolipids galactosylceramide and psychosine (galactosyl-sphingosine). Failure to break down these sphingolipids results in degeneration of the myelin sheath surrounding nerves in the brain (demyelination). Characteristic globoid cells appear in affected areas of the brain. This metabolic disorder is characterized by progressive neurological dysfunction with irritability, developmental regression, abnormal body tone, seizures and peripheral neuropathy. The MRI may appear normal early in the disease course but eventually demonstrates diffuse white matter abnormalities. More than 75 mutations have been described in the GALC gene. There is limited correlation between genotype and phenotype, with the exception of homozygosity for the common 30kb deletion being predictive of early-infantile Krabbe disease and having at least one G809A allele being compatible with juvenile or adult onset. Otherwise, the genotype–phenotype correlation is poor, making prediction of the early-infantile phenotype at birth difficult. The incidence of Krabbe disease has been estimated at 1 in 100,000, with 85 to 90% of patients having the early-infantile form, although recent newborn screening results suggest that a higher proportion of patients may have later onset forms. Early hematopoietic stem cell transplantation attenuates the clinical course of infantile Krabbe disease and prolongs survival but is not curative.Megalencephalic leukoencephalopathy with subcortical cysts
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive condition which initially presents with macrocephaly (enlarged head size). Mild motor delay is followed by gradual motor deterioration with ataxia and spasticity. Cognitive abilities are relatively spared but seizures may occur in this classical form. Recessive MLC1 mutations are observed in 80% of patients with MLC. Other patients with the classical, deteriorating phenotype have two mutations in the HEPACAM gene. An improving phenotype has been described in patients with only one mutation in HEPACAM. Most parents with a single mutation had macrocephaly, indicating dominant inheritance. In some families with dominant HEPACAM mutations, the clinical picture and magnetic resonance imaging normalized, indicating that HEPACAM mutations can cause benign familial macrocephaly. In other families with dominant HEPACAM mutations, patients had macrocephaly and intellectual disability with or without autism. Diffuse white matter abnormalities on MRI are accompanied by anterior temporal cysts.Metachromatic leukodystrophy
Metachromatic leukodystrophy is an autosomal recessive lysosomal storage disease caused by the deficiency of arylsulphatase A (ASA). This leads to the accumulation of a fatty substance known as sulfatide, sphingolipid, in the brain and other areas of the body (i.e., liver, gall bladder, kidneys, and/or spleen). Myelin is lost from areas of the central nervous system and peripheral nerves due to the buildup of sulfatide. Symptoms of metachromatic leukodystrophy may include seizures, personality changes, spasticity, progressive dementia, painful paresthesias, motor disturbances progressing to paralysis, and/or visual impairment leading to blindness. Infantile, juvenile, and adult onset forms of metachromatic leukodystrophy have been distinguished. There is evidence for genotype-phenotype correlation. Patients with 2 mutations that do not allow expression of the ASA enzyme suffer from the late infantile form whereas the juvenile patients have more residual enzyme activity. ASA-deficient mice have been produced which have led to a better understanding of the disease process and to various therapeutic trials involving enzyme replacement therapy, haematopoietic stem-cell transplant and gene therapy.Multiple sulfatase deficiency
Multiple sulfatase deficiency (MSD) is a very rare leukodystrophy in which all of the known sulfatase enzymes (thought to be seven in number) are deficient or inoperative due to mutations in the SUMF1 gene. Major symptoms include mildly coarsened facial features, deafness, and an enlarged liver and spleen (hepatosplenomegaly). Abnormalities of the skeleton may occur, such as curvature of the spine (lumbar kyphosis) and the breast bone. The skin is usually dry and scaly (ichthyosis). Before symptoms are noticeable, children with this disorder usually develop more slowly than normal. They may not learn to walk or speak as quickly as other children.Similar to metachromatic leukodystrophy, multiple sulfatase deficiency patients exhibit neurodegenerative disease in early childhood due to central nervous system (CNS) and peripheral demyelination with loss of sensory and motor functions. They also develop intellectual disability, hepatosplenomegaly, coarse facies, and corneal clouding as seen in patients with mucopolysaccharidoses. Ichthyosis and skeletal changes reflect enzyme deficiencies of steroid sulfatase (X-linked ichthyosis) and arylsulfatase E (chondrodysplasia punctata), respectively. The unique combination of neurodegeneration, coarse facial features, hepatosplenomegaly, and ichthyosis is not seen in other neuro-ichthyotic disorders. However, the sequential appearance of these clinical signs often delays the diagnosis of MSD.Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease, also known as X-linked spastic paraplegia, is a rare inherited disorder affecting the central nervous system that is associated with a lack of myelin sheath. Many areas of the central nervous system may be affected, including the deep portions of the cerebrum (subcortical), cerebellum, and/or brain stem. Symptoms may include the impaired ability to coordinate movement (ataxia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs, delays in reaching developmental milestones, loss of motor abilities, and the progressive deterioration of intellectual function. The symptoms of Pelizaeus-Merzbacher disease (PMD) are usually slowly progressive. Several forms of the disorder have been identified, including classical X-linked PMD; acute infantile (or connatal) PMD; and adult-onset (or late-onset) PMD. Various types of mutations of the X-linked proteolipid protein 1 gene (PLP1) that include copy number changes, point mutations, and insertions or deletions of a few bases lead to a clinical spectrum from the most severe connatal PMD, to the least severe spastic paraplegia 2 (SPG2). The most common form of PMD is caused by a duplication of the PLP1 gene and affects males. Signs of PMD include nystagmus, hypotonia, tremors, titubation, ataxia, spasticity, athetotic movements and cognitive impairment; the major findings in SPG2 are leg weakness and spasticity. Supportive therapy for patients with PMD/SPG2 includes medications for seizures and spasticity; physical therapy, exercise, and orthotics for spasticity management; surgery for contractures and scoliosis; gastrostomy for severe dysphagia; proper wheelchair seating, physical therapy, and orthotics to prevent or ameliorate the effects of scoliosis; special education; and assistive communication devices.An autosomal recessive condition clinically resembling classical PMD, PMD-like disease, has been described due to mutations in gap junction protein (GJA12). This condition affects both males and females.Pol III-Related Leukodystrophies
The Pol III-related leukodystrophies comprise a group of 5 overlapping clinically defined hypomyelinating leukodystrophies including: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH);Leukodystrophy with oligodontia (LO); and Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). These conditions present with varying combinations of motor dysfunction, abnormal teeth and hypogonadotropic hypogonadism. The MRI scan of the brain demonstrates hypomyelination. The condition is associated with autosomal recessive mutations in POLR3A or POLR3B.Refsum disease
Refsum disease, also called hereditary sensory motor neuropathy type IV, is an autosomal recessive leukodystrophy in which the myelin sheath fails to grow. The disorder is caused by the accumulation of a methyl branched chain fatty acid (phytanic acid) in blood plasma and tissues due to mutations in the PHYH gene that encodes the peroxisomal enzyme phytanoyl-CoA hydroxylase that is responsible for the a-oxidation of phytanic acid. 90% of patients with Refsum disease have a mutation in the PHYH gene; whereas the remaining 10% have a mutation in the peroxisomal gene, Pex7, which is necessary for import of phytanoyl-CoA hydroxylase into peroxisomes. Refsum disease is characterized by progressive loss of vision (retinitis pigmentosa); degenerative nerve disease (peripheral neuropathy); failure of muscle coordination (ataxia); and dry, rough, scaly skin (ichthyosis). Treatment with a diet low in phytanic acid and avoidance of foods such as cold water fish, dairy and ruminant meats that contain phytanic acid can be beneficial. Plasmapheresis and the intestinal lipase inhibitor, Orlistat have shown some efficacy in lowering phytanic acid levels. However these therapies, while successful at diminishing the neurological symptoms do not prevent the slow progression of retinitis pigmentosa.Salla disease
Salla disease is a rare autosomal recessive disorder due to deficiency of the sialic acid transporter, SLC17A5. Free sialic acid (N-acetylneuraminic acid) accumulates in lysosomes in various tissues. The severe form, infantile free sialic acid storage disorder, results in early death. Salla’s disease, which is more common in patients of Finnish descent, has wide clinical variability. Most children present between 3 and 9 months of age with hypotonia, ataxia, delayed motor milestones, and transient nystagmus. Cognitive delay and slow motor decline occurs after the second to third decade. Peripheral neuropathy may be present and contribute to motor disability. MRI findings are consistent with hypomyelination with minimal or extremely slow myelination. Myelin is present in the internal capsule and is usually normal in the cerebellum. The corpus callosum is usually thin. Treatment for Salla’s disease is supportive.Sjögren-Larsson syndrome
Sjögren-Larsson syndrome (SLS) is caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase is located on chromosome 17p11.2. More than 70 different mutations in the ALDH3A2 gene have been identified in SLS patients originating from about 120 different families. Fatty aldehyde dehydrogenase is necessary for the oxidation of long-chain aldehydes and alcohols to fatty acids. Deficiency of this enzyme leads to accumulation of these lipids leading to increased inflammatory lipids, the leukotrienes, in skin and brain, which are thought to be directly responsible for the symptoms of ichthyosis and delay in myelination. About 70% of SLS patients are born preterm most likely due to the fetal excretion of abnormal lipids and leukotrienes causing inflammation and early labor. During early childhood (1–2 years of age) intellectual and motor disabilities gradually become clear, however, the typical MRI and H-MRS abnormalities, as well as crystalline maculopathy, may be absent, and normal radiologic and ocular findings do not exclude SLS at this stage. Later on in childhood (from 3 years of age), the full-blown phenotype of SLS with the classical triad of ichthyosis, spasticity, and intellectual disability is present with the typical findings of ophthalmological and MRI/H-MRS studies. Therapies consist of preventing skin lesions through application of special creams and urea-containing emollients and physical therapy and bracing to diminish contractures. Therapies to reduce the levels of leukotrienes, to prevent the skin lesions and improve neurological functioning are being studied.X-linked adrenoleukodystrophy
X-linked adrenoleukodystrophy (ALD) is the most common leukodystrophy and affects the myelin or white matter of the brain and the spinal cord as well as the adrenal cortex. The gene for ALD, the ABCD1 gene, is located at Xq28 and encodes a peroxisomal protein belonging to the ATPase Binding Cassette proteins. There have been more than 1000 mutations reported in the ABCD1 gene (www.x-ald.nl). ALD is a progressive disease characterized by an accumulation of very long chain fatty acids, mainly of 26 carbons in chain length. There are several phenotypes of ALD, each distinguished by the age of onset and by the features that are present. All phenotypes can occur in the same kindred with 31-35% of affected males having the demyelinating childhood cerebral form (CCER) with typical onset between 4 and 8 yrs. Boys develop normally until the onset of cognitive decline and progressive neurologic deficits which lead to a vegetative state, blindness, seizures and death often within 3 yrs. Forty to 46% of males with ALD present in early adulthood with slowly progressive paraparesis (weakness and spasticity), sensory, and sphincter disturbances involving spinal cord long tracts. This form is called adrenomyeloneuropathy (AMN). At least 30% of men with AMN develop cerebral involvement that is similar to CCER. Fifty per cent of heterozygous females (carriers) develop overt neurologic disturbances resembling AMN, with a mean age of onset of 37 yrs. The minimum frequency of hemizygotes (i.e., affected males) identified in the United States is estimated at 1:21,000 and that of hemizygotes plus heterozygotes (i.e., carrier females) 1:16,800.Untreated adrenal insufficiency can be fatal and occurs independent of neurological symptoms. Earlier onset of CCER correlates with more severe, rapidly progressive clinical manifestations. Boys with parieto-occipital lobe disease demonstrate visual and/or auditory processing abnormalities, impaired communication skills and gait disturbances prior to death. Boys with frontal lobe involvement have signs/symptoms similar to ADHD and are often misdiagnosed prior to death. The extent of demyelination can be quantitated using the MRI severity score of Loes.ALD in boys can be diagnosed by analysis of the very long chain fatty acids in plasma and if positive, mutation analysis of the ABCD1 gene is recommended. For females at risk of ALD, the most accurate test is targeted analysis of the family mutation in the ABCD1 gene as the plasma very long chain fatty acid test for females has a 20% false negative rate due to lyonization (selective X-inactivation) of the X-chromosome. It is important to screen all at-risk relatives for ALD as the males with ALD are at risk for Addison disease which is treatable with life-saving hormone therapy. Dietary therapy with Lorenzo’s oil if started early before MRI abnormalities occur and if plasma levels of very long chain fatty acids are normalized, has shown to statistically lower the development of CCER. Over one third of ALD boys will develop CCER thus ALD boys who are diagnosed before neurological symptoms occur should be followed by a pediatric neurologist and have MRI every 6 months. At first signs of progressive white matter abnormalities on MRI, bone marrow transplantation, or hematopoetic cell transplantation (HCT), is recommended as the only effective long-term treatment for CCER; however, to achieve optimal survival and clinical outcomes, HCT must occur prior to manifestations of symptoms. Gene therapy experimental treatment has been shown to be safe and efficacious.With the development of a newborn screening test for ALD all boys with ALD will be diagnosed at an age before Addison disease and brain dysfunction occur. Thus life-saving therapies can be implemented early and other at risk relatives identified.Zellweger syndrome spectrum disorders
Zellweger syndrome spectrum disorders, also known as peroxisomal biogenesis disorders (PBDs), are characterized by a deficiency or absence of peroxisomes in the cells of the liver, kidneys, and brain. Peroxisomes are very small, membrane-bound structures within the cytoplasm of cells that function as part of the body’s waste disposal system. In the absence of the enzymes normally found in peroxisomes, waste products, especially very long chain fatty acids (VLCFA), accumulate in the cells of the affected organ. The accumulation of these waste products has profound effects on the development of the fetus. PBDs are inherited as autosomal recessive disorders and have two clinically distinct subtypes: the Zellweger syndrome spectrum (ZSS) disorders and rhizomelic chondrodysplasia punctata (RCDP) type 1. PBDs are caused by defects in any of at least 14 different PEX genes, which encode proteins involved in peroxisome assembly and proliferation. There is genetic heterogeneity among PBDs and this is present in all defective PEX genes. The PBDs with the mildest phenotype are known by the clinical names, neonatal adrenoleukodystrophy and infantile Refsum’s disease. A range of symptoms are seen including developmental delay, sensorineural hearing loss, visual abnormalities, adrenal insufficiency and liver dysfunction. MRI scans may show developmental abnormalities of the brain and progressive white matter changes may develop. Diagnosis of PBDs is made by finding an increase in the plasma very long chain fatty acids (VLCFA) and the branched chain fatty acids, phytanic and pristanic. Additional biochemical laboratory tests are the measurement of red blood cell plasmalogens.
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Leukodystrophy
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Causes of Leukodystrophy
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Leukodystrophies are genetic disorders caused by specific gene abnormalities that lead to abnormal development or destruction of the myelin sheath in the nervous system or white matter in the brain. Each type of leukodystrophy follows a particular pattern of inheritance such as autosomal recessive, X-linked recessive or autosomal dominant. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry 10-15 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual (de novo mutation). The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene but may display milder symptoms (ex. AMN). Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Causes of Leukodystrophy. Leukodystrophies are genetic disorders caused by specific gene abnormalities that lead to abnormal development or destruction of the myelin sheath in the nervous system or white matter in the brain. Each type of leukodystrophy follows a particular pattern of inheritance such as autosomal recessive, X-linked recessive or autosomal dominant. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.All individuals carry 10-15 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual (de novo mutation). The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene but may display milder symptoms (ex. AMN). Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
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Leukodystrophy
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Affects of Leukodystrophy
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The leukodystrophies can affect either adults or children, but are more common in children. Some types of leukodystrophy affect males and females equally but other types predominantly affect males.
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Affects of Leukodystrophy. The leukodystrophies can affect either adults or children, but are more common in children. Some types of leukodystrophy affect males and females equally but other types predominantly affect males.
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Leukodystrophy
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Related disorders of Leukodystrophy
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Symptoms of the following disorder can be similar to those of leukodystrophy. Comparisons may be useful for a differential diagnosis:Multiple sclerosis (MS) is a chronic inflammatory disease affecting the myelin sheath of the brain and spinal cord (central nervous system). It may be progressive, relapsing and remitting, or stable. MS consists of small lesions called plaques that form randomly throughout the brain and spinal cord. These plaques on the myelin sheath prevent proper transmission of nervous system signals. White matter lesions in leukodystrophies tend to be more symmetric and confluent then in MS which may help distinguish the two conditions. Symptoms may include visual and speech problems, numbness, walking difficulty and loss of bladder or bowel control. MS affects both children and adults, and its cause is unknown.
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Related disorders of Leukodystrophy. Symptoms of the following disorder can be similar to those of leukodystrophy. Comparisons may be useful for a differential diagnosis:Multiple sclerosis (MS) is a chronic inflammatory disease affecting the myelin sheath of the brain and spinal cord (central nervous system). It may be progressive, relapsing and remitting, or stable. MS consists of small lesions called plaques that form randomly throughout the brain and spinal cord. These plaques on the myelin sheath prevent proper transmission of nervous system signals. White matter lesions in leukodystrophies tend to be more symmetric and confluent then in MS which may help distinguish the two conditions. Symptoms may include visual and speech problems, numbness, walking difficulty and loss of bladder or bowel control. MS affects both children and adults, and its cause is unknown.
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Leukodystrophy
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Diagnosis of Leukodystrophy
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Diagnosis of Leukodystrophy.
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Leukodystrophy
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Therapies of Leukodystrophy
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Treatment of most leukodystrophies is symptomatic and supportive. Medications and physical therapy may be helpful for spasticity and motor difficulties. Anti-epileptic medications should be provided for seizures and burning paresthesia from peripheral neuropathy may respond to medications for neuropathic pain. Please review the NORD report on the specific type of leukodystrophy for information about successful therapies. Genetic counseling is beneficial for affected individuals and their families.
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Therapies of Leukodystrophy. Treatment of most leukodystrophies is symptomatic and supportive. Medications and physical therapy may be helpful for spasticity and motor difficulties. Anti-epileptic medications should be provided for seizures and burning paresthesia from peripheral neuropathy may respond to medications for neuropathic pain. Please review the NORD report on the specific type of leukodystrophy for information about successful therapies. Genetic counseling is beneficial for affected individuals and their families.
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Leukodystrophy
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Overview of Leukodystrophy, Krabbe’s
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Krabbe's Leukodystrophy is a rare inherited lipid storage disorder caused by a deficiency of the enzyme galactocerebrosidase (GALC), which is necessary for the breakdown (metabolism) of the sphingolipids galactosylceremide and psychosine. Failure to break down these sphingolipids results in degeneration of the myelin sheath surrounding nerves in the brain (demyelination). Characteristic globoid cells appear in affected areas of the brain. This metabolic disorder is characterized by progressive neurological dysfunction such as intellectual disability, paralysis, blindness, deafness and paralysis of certain facial muscles (pseudobulbar palsy). Krabbe's Leukodystrophy is inherited as an autosomal recessive trait.
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Overview of Leukodystrophy, Krabbe’s. Krabbe's Leukodystrophy is a rare inherited lipid storage disorder caused by a deficiency of the enzyme galactocerebrosidase (GALC), which is necessary for the breakdown (metabolism) of the sphingolipids galactosylceremide and psychosine. Failure to break down these sphingolipids results in degeneration of the myelin sheath surrounding nerves in the brain (demyelination). Characteristic globoid cells appear in affected areas of the brain. This metabolic disorder is characterized by progressive neurological dysfunction such as intellectual disability, paralysis, blindness, deafness and paralysis of certain facial muscles (pseudobulbar palsy). Krabbe's Leukodystrophy is inherited as an autosomal recessive trait.
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Leukodystrophy, Krabbe’s
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Symptoms of Leukodystrophy, Krabbe’s
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Onset of Krabbe's Leukodystrophy in the predominant infantile form (90% of cases) occurs between one and seven months of age. A late-onset form of the disorder occurs at 18 months or a later age, including adolescence and adulthood. The specific symptoms and severity of Krabbe's Leukodystrophy vary from case to case. Infants affected by Krabbe's Leukodystrophy may be fretful and excessively irritable (hyperirritability). Vomiting, unexplained fevers, and partial unconsciousness are additional possible symptoms. The lower extremities may have spastic contractions. Seizures characterized by alternating contraction and relaxation (clonic), or by continuous tension (tonic), may also occur. Affected infants are hypersensitive to various stimuli such as sounds. Mental and physical development may be slow. Regression of previously acquired skills may occur in some cases. Because of degeneration of certain parts of the brain, the legs are sometimes rigidly extended at the hip and knee; the arms may be rotated at the shoulder and extended at the elbow; and the ankles, toes and fingers may be flexed (decerebrate rigidity). Blindness caused by brain cortex degeneration may also occur. Individuals with Krabbe's Leukodystrophy may also have difficulty swallowing (dysphagia) and peripheral neuropathy, a condition characterized by muscle weakness; pain; numbness; redness; and/or burning or tingling sensations in the affected areas, especially the arms and legs (extremities). Krabbe's Leukodystrophy often progresses to cause life-threatening complications. In the juvenile and adult forms of Krabbe's Leukodystrophy, the initial symptom may be impaired control of voluntary movements and progressive rigidity of muscles in the legs (spastic paraparesis). Affected individuals with these forms of the disorder may also experience progressive vision loss and disease affecting multiple nerves (polyneuropathy).
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Symptoms of Leukodystrophy, Krabbe’s. Onset of Krabbe's Leukodystrophy in the predominant infantile form (90% of cases) occurs between one and seven months of age. A late-onset form of the disorder occurs at 18 months or a later age, including adolescence and adulthood. The specific symptoms and severity of Krabbe's Leukodystrophy vary from case to case. Infants affected by Krabbe's Leukodystrophy may be fretful and excessively irritable (hyperirritability). Vomiting, unexplained fevers, and partial unconsciousness are additional possible symptoms. The lower extremities may have spastic contractions. Seizures characterized by alternating contraction and relaxation (clonic), or by continuous tension (tonic), may also occur. Affected infants are hypersensitive to various stimuli such as sounds. Mental and physical development may be slow. Regression of previously acquired skills may occur in some cases. Because of degeneration of certain parts of the brain, the legs are sometimes rigidly extended at the hip and knee; the arms may be rotated at the shoulder and extended at the elbow; and the ankles, toes and fingers may be flexed (decerebrate rigidity). Blindness caused by brain cortex degeneration may also occur. Individuals with Krabbe's Leukodystrophy may also have difficulty swallowing (dysphagia) and peripheral neuropathy, a condition characterized by muscle weakness; pain; numbness; redness; and/or burning or tingling sensations in the affected areas, especially the arms and legs (extremities). Krabbe's Leukodystrophy often progresses to cause life-threatening complications. In the juvenile and adult forms of Krabbe's Leukodystrophy, the initial symptom may be impaired control of voluntary movements and progressive rigidity of muscles in the legs (spastic paraparesis). Affected individuals with these forms of the disorder may also experience progressive vision loss and disease affecting multiple nerves (polyneuropathy).
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Leukodystrophy, Krabbe’s
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Causes of Leukodystrophy, Krabbe’s
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Krabbe's Leukodystrophy is a hereditary disorder transferred to offspring through recessive genes. It is caused by a deficiency of the enzyme galactoside beta-galactosidase (galactosyl ceramidase). This enzyme is needed for the metabolism of galactocerebroside (galactosyl ceramide), a component of the fatty sheath around the nerves (myelin). The demyelination of the nerve cells in the large hemispheres of the brain (and in the brain stem) causes the neurological symptoms of Krabbe's Leukodystrophy.Human 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 recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.Investigators have determined that Krabbe's Leukodystrophy may be caused by disruption or changes (mutations) of the human galactocerebrosidase (GALC) gene located on the long arm (q) of chromosome 14 (14q31). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, “chromosome 14q31” refers to band 31 on the long arm of chromosome 14.
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Causes of Leukodystrophy, Krabbe’s. Krabbe's Leukodystrophy is a hereditary disorder transferred to offspring through recessive genes. It is caused by a deficiency of the enzyme galactoside beta-galactosidase (galactosyl ceramidase). This enzyme is needed for the metabolism of galactocerebroside (galactosyl ceramide), a component of the fatty sheath around the nerves (myelin). The demyelination of the nerve cells in the large hemispheres of the brain (and in the brain stem) causes the neurological symptoms of Krabbe's Leukodystrophy.Human 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 recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.Investigators have determined that Krabbe's Leukodystrophy may be caused by disruption or changes (mutations) of the human galactocerebrosidase (GALC) gene located on the long arm (q) of chromosome 14 (14q31). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, “chromosome 14q31” refers to band 31 on the long arm of chromosome 14.
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Leukodystrophy, Krabbe’s
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Affects of Leukodystrophy, Krabbe’s
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About 1 in 100,000 newborn babies in the United States is affected with Krabbe's Leukodystrophy. Males are affected as often as females.
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Affects of Leukodystrophy, Krabbe’s. About 1 in 100,000 newborn babies in the United States is affected with Krabbe's Leukodystrophy. Males are affected as often as females.
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Related disorders of Leukodystrophy, Krabbe’s
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Symptoms of the following disorders can be similar to those of Krabbe's Leukodystrophy. Comparisons may be useful for a differential diagnosis:Adrenoleukodystrophy (ALD, or Schilder's Disease) is one of many different leukodystrophies. The disorder may appear in two distinct genetic forms: sex-linked and Neonatal ALD. Both are characterized by destruction of the lipid sheaths surrounding the nerves (demyelination) in the brain. However, they differ in the mode of inheritance, severity and type of symptoms. All types of ALD are characterized by an accumulation of Very Long Chain Fatty Acids (VLCFA), which is a type of fat molecule that accumulates in the body's tissues, especially in the adrenal gland and the white matter of the brain. An accumulation of lymph and plasma cells around the blood vessels in the central nervous system may also occur. (For more information on this disorder, choose “adrenoleukodystrophy” as your search term in the Rare Disease Database).Canavan's Leukodystrophy (Spongy Degeneration of the Brain) is a form of leukodystrophy that causes the white matter of the brain to be replaced by microscopic fluid-filled spaces. This disorder, a hereditary disease in children, is characterized by structural abnormalities and deterioration of motor, sensory, and intellectual functions. It seems to affect persons of Eastern European Jewish ancestry most frequently. The disorder is progressive and degenerative. Symptoms may include progressive mental decline accompanied by the loss of muscle tone, poor head control, an abnormally enlarged head (megalocephaly), and/or blindness. (For more information on this disorder, choose “Canavan's Leukodystrophy” as your search term in the Rare Disease Database.)Metachromatic Leukodystrophy (MLD), the most common form of leukodystrophy, is a rare inherited neurometabolic disorder affecting the white matter of the brain (leukoencephalopathy). It is characterized by the accumulation of a fatty substance known as sulfatide (a sphingolipid) in the brain and other areas of the body (i.e., liver, gall bladder, kidneys, and/or spleen). The fatty protective covering on the nerve fibers (myelin) is lost from areas of the central nervous system (CNS) due to the buildup of sulfatide. Symptoms of Metachromatic Leukodystrophy may include convulsions, seizures, personality changes, spasticity, progressive dementia, motor disturbances progressing to paralysis, and/or visual impairment leading to blindness. Metachromatic Leukodystrophy is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Metachromatic Leukodystrophy” as your search term in the Rare Disease Database).Alexander Disease is an extremely rare, progressive, neurological disorder that usually becomes apparent during infancy or early childhood. However, less commonly, cases have been described in which symptom onset has occurred in later childhood or adolescence (juvenile onset) or, rarely, during the third to fifth decades of life (adult onset). In infants and young children affected by Alexander Disease, associated symptoms and findings include a failure to grow and gain weight at the expected rate (failure to thrive); delays in the development of certain physical, mental, and behavioral skills that are typically acquired at particular stages (psychomotor retardation); and progressive enlargement of the head (macrocephaly). Additional features typically include sudden episodes of uncontrolled electrical activity in the brain (seizures); abnormally increased muscle stiffness and restriction of movement (spasticity); and progressive neurological deterioration. In some cases, there is hydrocephalus. In most cases, Alexander Disease appears to occur randomly for unknown reasons (sporadically), with no family history of the disease. In an extremely small number of cases, it is thought that the disorder may have affected more than one family member. (For more information on this disorder, choose “Alexander” as your search term in the Rare Disease Database).
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Related disorders of Leukodystrophy, Krabbe’s. Symptoms of the following disorders can be similar to those of Krabbe's Leukodystrophy. Comparisons may be useful for a differential diagnosis:Adrenoleukodystrophy (ALD, or Schilder's Disease) is one of many different leukodystrophies. The disorder may appear in two distinct genetic forms: sex-linked and Neonatal ALD. Both are characterized by destruction of the lipid sheaths surrounding the nerves (demyelination) in the brain. However, they differ in the mode of inheritance, severity and type of symptoms. All types of ALD are characterized by an accumulation of Very Long Chain Fatty Acids (VLCFA), which is a type of fat molecule that accumulates in the body's tissues, especially in the adrenal gland and the white matter of the brain. An accumulation of lymph and plasma cells around the blood vessels in the central nervous system may also occur. (For more information on this disorder, choose “adrenoleukodystrophy” as your search term in the Rare Disease Database).Canavan's Leukodystrophy (Spongy Degeneration of the Brain) is a form of leukodystrophy that causes the white matter of the brain to be replaced by microscopic fluid-filled spaces. This disorder, a hereditary disease in children, is characterized by structural abnormalities and deterioration of motor, sensory, and intellectual functions. It seems to affect persons of Eastern European Jewish ancestry most frequently. The disorder is progressive and degenerative. Symptoms may include progressive mental decline accompanied by the loss of muscle tone, poor head control, an abnormally enlarged head (megalocephaly), and/or blindness. (For more information on this disorder, choose “Canavan's Leukodystrophy” as your search term in the Rare Disease Database.)Metachromatic Leukodystrophy (MLD), the most common form of leukodystrophy, is a rare inherited neurometabolic disorder affecting the white matter of the brain (leukoencephalopathy). It is characterized by the accumulation of a fatty substance known as sulfatide (a sphingolipid) in the brain and other areas of the body (i.e., liver, gall bladder, kidneys, and/or spleen). The fatty protective covering on the nerve fibers (myelin) is lost from areas of the central nervous system (CNS) due to the buildup of sulfatide. Symptoms of Metachromatic Leukodystrophy may include convulsions, seizures, personality changes, spasticity, progressive dementia, motor disturbances progressing to paralysis, and/or visual impairment leading to blindness. Metachromatic Leukodystrophy is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Metachromatic Leukodystrophy” as your search term in the Rare Disease Database).Alexander Disease is an extremely rare, progressive, neurological disorder that usually becomes apparent during infancy or early childhood. However, less commonly, cases have been described in which symptom onset has occurred in later childhood or adolescence (juvenile onset) or, rarely, during the third to fifth decades of life (adult onset). In infants and young children affected by Alexander Disease, associated symptoms and findings include a failure to grow and gain weight at the expected rate (failure to thrive); delays in the development of certain physical, mental, and behavioral skills that are typically acquired at particular stages (psychomotor retardation); and progressive enlargement of the head (macrocephaly). Additional features typically include sudden episodes of uncontrolled electrical activity in the brain (seizures); abnormally increased muscle stiffness and restriction of movement (spasticity); and progressive neurological deterioration. In some cases, there is hydrocephalus. In most cases, Alexander Disease appears to occur randomly for unknown reasons (sporadically), with no family history of the disease. In an extremely small number of cases, it is thought that the disorder may have affected more than one family member. (For more information on this disorder, choose “Alexander” as your search term in the Rare Disease Database).
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Diagnosis of Leukodystrophy, Krabbe’s
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Krabbe's Leukodystrophy can be diagnosed by testing the activity of the enzyme galactocerebrosidase (galactosylceramidase) in fibroblast cells obtained from an infant or from a fetus by amniocentesis.
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Diagnosis of Leukodystrophy, Krabbe’s. Krabbe's Leukodystrophy can be diagnosed by testing the activity of the enzyme galactocerebrosidase (galactosylceramidase) in fibroblast cells obtained from an infant or from a fetus by amniocentesis.
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Therapies of Leukodystrophy, Krabbe’s
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TreatmentThere is no specific treatment for Krabbe's Leukodystrophy. Treatment is symptomatic and supportive. Genetic counseling may be helpful for families of children affected by this illness.
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Therapies of Leukodystrophy, Krabbe’s. TreatmentThere is no specific treatment for Krabbe's Leukodystrophy. Treatment is symptomatic and supportive. Genetic counseling may be helpful for families of children affected by this illness.
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Overview of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
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Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a rare disorder characterized by a range of neurological issues. Affected individuals have disease of the white matter of the brain (leukoencephalopathy). White matter forms what is known as the myelin sheath, which is the protective covering of the nerve fibers. Without white matter, the signals between nerve cells cannot be transmitted properly. Lactate is a metabolite found in the brain; it’s exact role in the brain is not fully understood but it may help to supply energy to nerve cells. Lactate is elevated in most individuals with LBSL. Affected individuals exhibit a variety of symptoms including spasticity, weakness and progressive cerebellar ataxia. Spasticity is stiffness of the muscles, which leads to progressive difficulty with walking and for some, loss of the ability to walk. Cerebellar ataxia is difficulty with coordinating voluntary movements, which can lead a variety of issues including poor manual coordination, difficulty with fine motor tasks, and unsteadiness when walking. LBSL is caused by an abnormal variant (mutation) in the DARS2 gene. There is no cure and treatment is aimed at the specific symptoms that are present.
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Overview of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation. Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a rare disorder characterized by a range of neurological issues. Affected individuals have disease of the white matter of the brain (leukoencephalopathy). White matter forms what is known as the myelin sheath, which is the protective covering of the nerve fibers. Without white matter, the signals between nerve cells cannot be transmitted properly. Lactate is a metabolite found in the brain; it’s exact role in the brain is not fully understood but it may help to supply energy to nerve cells. Lactate is elevated in most individuals with LBSL. Affected individuals exhibit a variety of symptoms including spasticity, weakness and progressive cerebellar ataxia. Spasticity is stiffness of the muscles, which leads to progressive difficulty with walking and for some, loss of the ability to walk. Cerebellar ataxia is difficulty with coordinating voluntary movements, which can lead a variety of issues including poor manual coordination, difficulty with fine motor tasks, and unsteadiness when walking. LBSL is caused by an abnormal variant (mutation) in the DARS2 gene. There is no cure and treatment is aimed at the specific symptoms that are present.
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Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
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Symptoms of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
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Although researchers have been able to establish some characteristic or “core” symptoms that define LBSL, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the fact that many combinations of mutation types can produce this disorder prevent 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. Affected individuals or parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.LBSL is best thought of as a spectrum of disease. It can cause symptoms that develop before birth (neonatally) with severe complications in infancy. Often, newborns or infants who develop symptoms early in infancy pass away within the first couple years of life. Conversely, some individuals may not develop noticeable symptoms until school age or adulthood and these symptoms may remain mild for many years. Except for the most severe form, LBSL usually develops slowly over years. In most individuals with childhood onset of this disorder, initial development is normal. Most children will walk within a normal age range, but many will require assistance to walk by their teen-age years, their 20s, or later in adulthood. Some will require the use of a wheelchair. The onset, progression and severity will vary. Some individuals may have mild balance problems in their teens that become difficulties with walking (gait disturbance). Most individuals with adult onset of the disorder do not become reliant on a wheelchair. The most common symptoms experienced in LBSL are spasticity, or stiffness of the muscles, and cerebellar ataxia, which is difficulty coordinating walking and executing fine motor skills. Affected individuals may also have problems sensing the position of their arms and legs. The legs tend to be more severely affected than the arms. Additional symptoms that can occur include seizures, difficulty speaking (dysarthria), hand tremors, rapid, involuntary eye movements (nystagmus), and a decline in cognitive skills, although most affected individuals have normal intellectual abilities. Some children may experience learning disabilities. Sometimes, peripheral neuropathy develops. This a condition that occurs when nerves that carry messages to and from the brain and spinal cord to the rest of the body are damaged. Those affected may experience tingling, burning, numbness, and stabbing pain in the affected extremities. Individuals with LBSL may be at risk for severe complications following minor head trauma. Minor head trauma can cause loss of consciousness, fever, and neurological decline.
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Symptoms of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation. Although researchers have been able to establish some characteristic or “core” symptoms that define LBSL, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the fact that many combinations of mutation types can produce this disorder prevent 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. Affected individuals or parents of affected children should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.LBSL is best thought of as a spectrum of disease. It can cause symptoms that develop before birth (neonatally) with severe complications in infancy. Often, newborns or infants who develop symptoms early in infancy pass away within the first couple years of life. Conversely, some individuals may not develop noticeable symptoms until school age or adulthood and these symptoms may remain mild for many years. Except for the most severe form, LBSL usually develops slowly over years. In most individuals with childhood onset of this disorder, initial development is normal. Most children will walk within a normal age range, but many will require assistance to walk by their teen-age years, their 20s, or later in adulthood. Some will require the use of a wheelchair. The onset, progression and severity will vary. Some individuals may have mild balance problems in their teens that become difficulties with walking (gait disturbance). Most individuals with adult onset of the disorder do not become reliant on a wheelchair. The most common symptoms experienced in LBSL are spasticity, or stiffness of the muscles, and cerebellar ataxia, which is difficulty coordinating walking and executing fine motor skills. Affected individuals may also have problems sensing the position of their arms and legs. The legs tend to be more severely affected than the arms. Additional symptoms that can occur include seizures, difficulty speaking (dysarthria), hand tremors, rapid, involuntary eye movements (nystagmus), and a decline in cognitive skills, although most affected individuals have normal intellectual abilities. Some children may experience learning disabilities. Sometimes, peripheral neuropathy develops. This a condition that occurs when nerves that carry messages to and from the brain and spinal cord to the rest of the body are damaged. Those affected may experience tingling, burning, numbness, and stabbing pain in the affected extremities. Individuals with LBSL may be at risk for severe complications following minor head trauma. Minor head trauma can cause loss of consciousness, fever, and neurological decline.
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Causes of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
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LBSL is caused by an abnormal variant on in the DARS2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain and spinal cord.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a recessive pattern occur when an individual inherits the same abnormal gene for the same trait from each parent. Nearly all individuals with LBSL are compound heterozygous for two DARS2 mutations, which means they have actually inherited 2 different autosomal recessive mutations that have the combined effect of causing disease. The DARS2 gene produces an enzyme called mitochondrial aspartyl-tRNA synthetase. Enzymes are specialized proteins that act to bring about biochemical reactions. The mitochondrial aspartyl-tRNA synthetase enzyme acts to combine the amino acid aspartic acid with mitochondrial proteins. Mitochondria, found by the hundreds within virtually every cell of the body, are often described as the powerhouses of the cell. They generate most of the cellular energy through respiratory chain enzymes, which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. Because of the mutations affecting the DARS2 gene, there is insufficient production of functional mitochondrial aspartyl-tRNA synthetase, which impacts the binding of aspartic acid to mitochondrial proteins. How these changes ultimately lead to the signs and symptoms of LBSL is not fully understood.
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Causes of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation. LBSL is caused by an abnormal variant on in the DARS2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain and spinal cord.Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a recessive pattern occur when an individual inherits the same abnormal gene for the same trait from each parent. Nearly all individuals with LBSL are compound heterozygous for two DARS2 mutations, which means they have actually inherited 2 different autosomal recessive mutations that have the combined effect of causing disease. The DARS2 gene produces an enzyme called mitochondrial aspartyl-tRNA synthetase. Enzymes are specialized proteins that act to bring about biochemical reactions. The mitochondrial aspartyl-tRNA synthetase enzyme acts to combine the amino acid aspartic acid with mitochondrial proteins. Mitochondria, found by the hundreds within virtually every cell of the body, are often described as the powerhouses of the cell. They generate most of the cellular energy through respiratory chain enzymes, which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. Because of the mutations affecting the DARS2 gene, there is insufficient production of functional mitochondrial aspartyl-tRNA synthetase, which impacts the binding of aspartic acid to mitochondrial proteins. How these changes ultimately lead to the signs and symptoms of LBSL is not fully understood.
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Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
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Affects of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
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LBSL is an extremely rare disorder that was first reported in the medical literature in 2002. According to the nonprofit organization, A Cure for Ellie, as of April 2018, there are about 100 individuals worldwide who have been identified with the disorder. Because rare diseases like LBSL often go undiagnosed or misdiagnosed, it is difficult to determine the true frequency in the general population.
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Affects of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation. LBSL is an extremely rare disorder that was first reported in the medical literature in 2002. According to the nonprofit organization, A Cure for Ellie, as of April 2018, there are about 100 individuals worldwide who have been identified with the disorder. Because rare diseases like LBSL often go undiagnosed or misdiagnosed, it is difficult to determine the true frequency in the general population.
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Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
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Related disorders of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
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Symptoms of the following disorders can be similar to those of LBSL. Comparisons may be useful for a differential diagnosis.Mitochondrial diseases are a group of rare genetic disorders. Mitochondria, found by the hundreds within virtually every cell of the body, are often described as the powerhouses of the cell. They generate most of the cellular energy through the respiratory chain enzymes (complexes I-V), which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. The genetic blueprints for essential components of the respiratory chain are mitochondrial DNA (mtDNA). Disorders due to mitochondrial dysfunction, often defects of the respiratory chain, are called mitochondrial diseases. Because energy is essential for many tissue functions, mitochondrial diseases typically affect multiple organs of the body. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) The hereditary ataxias are a group of neurological disorders of varying degrees of rarity that are characterized by degenerative changes in the brain and spinal cord that lead to an awkward, uncoordinated walk (gait) accompanied often by poor eye-hand coordination and abnormal speech (dysarthria). Hereditary ataxia in one or another of its forms may present at almost any time between infancy and adulthood. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation. Symptoms of the following disorders can be similar to those of LBSL. Comparisons may be useful for a differential diagnosis.Mitochondrial diseases are a group of rare genetic disorders. Mitochondria, found by the hundreds within virtually every cell of the body, are often described as the powerhouses of the cell. They generate most of the cellular energy through the respiratory chain enzymes (complexes I-V), which convert electrons derived from sugars and fats into ATP, the energy currency of the cell. The genetic blueprints for essential components of the respiratory chain are mitochondrial DNA (mtDNA). Disorders due to mitochondrial dysfunction, often defects of the respiratory chain, are called mitochondrial diseases. Because energy is essential for many tissue functions, mitochondrial diseases typically affect multiple organs of the body. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.) The hereditary ataxias are a group of neurological disorders of varying degrees of rarity that are characterized by degenerative changes in the brain and spinal cord that lead to an awkward, uncoordinated walk (gait) accompanied often by poor eye-hand coordination and abnormal speech (dysarthria). Hereditary ataxia in one or another of its forms may present at almost any time between infancy and adulthood. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
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Diagnosis of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
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A diagnosis of LBSL is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including genetic testing to determine mutations in the DARS2 gene. Clinical Testing and Workup
Distinctive findings can be found on a specialized imaging technique called magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Specifically, there are distinctive changes on MRIs of certain areas of the brain or spinal cord that can be used to diagnose LBSL. Some publications suggest that proton magnetic resonance spectroscopy be used to detect lactate, which is elevated in abnormal white matter sections in most but not all affected individuals. This noninvasive test is a specialized imaging technique that allows physicians to assessed changes in brain biochemistry. However, because not every patient shows elevated lactate levels, LBSL should be suspected if characteristic MRI findings are present whether lactate levels are elevated or not. Molecular genetic testing can confirm a diagnosis of LBSL. Molecular genetic testing can detect abnormal variations in the DARS2 gene, but is available only as a diagnostic service at specialized laboratories.
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Diagnosis of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation. A diagnosis of LBSL is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including genetic testing to determine mutations in the DARS2 gene. Clinical Testing and Workup
Distinctive findings can be found on a specialized imaging technique called magnetic resonance imaging (MRI). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. Specifically, there are distinctive changes on MRIs of certain areas of the brain or spinal cord that can be used to diagnose LBSL. Some publications suggest that proton magnetic resonance spectroscopy be used to detect lactate, which is elevated in abnormal white matter sections in most but not all affected individuals. This noninvasive test is a specialized imaging technique that allows physicians to assessed changes in brain biochemistry. However, because not every patient shows elevated lactate levels, LBSL should be suspected if characteristic MRI findings are present whether lactate levels are elevated or not. Molecular genetic testing can confirm a diagnosis of LBSL. Molecular genetic testing can detect abnormal variations in the DARS2 gene, but is available only as a diagnostic service at specialized laboratories.
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Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
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Therapies of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
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There is no cure for LBSL. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, specialists in diagnosing and treating disorder of the brain and central nervous system in children (neurologists), physical therapists, geneticists, social workers and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or a small series of reports. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with LBSL. Affected individuals may benefit from physical therapy and rehabilitation, which can improve motor function. Speech therapy can help individuals with dysarthria. Additional medical, social, and/or vocation services including special remedial education may be necessary. Anti-seizure medications, called anti-convulsants or anti-epileptics, may be prescribed for seizures. LBSL is usually a slowly progressive disorder and follow-up MRIs every few years is recommended.
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Therapies of Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation. There is no cure for LBSL. Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, specialists in diagnosing and treating disorder of the brain and central nervous system in children (neurologists), physical therapists, geneticists, social workers and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families. There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or a small series of reports. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with LBSL. Affected individuals may benefit from physical therapy and rehabilitation, which can improve motor function. Speech therapy can help individuals with dysarthria. Additional medical, social, and/or vocation services including special remedial education may be necessary. Anti-seizure medications, called anti-convulsants or anti-epileptics, may be prescribed for seizures. LBSL is usually a slowly progressive disorder and follow-up MRIs every few years is recommended.
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Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
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Overview of Levy-Yeboa Syndrome
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Levy-Yeboa syndrome (LYS) is a recently recognized, inherited (congenital), multi-system disorder involving signs of musculoskeletal involvement such as low muscle tone and stiffening of the joints of the arms and legs (contractions), loss of hearing (neuronal deafness), intense burn-like eruptions of the skin containing clear fluid (bullous eruptions) and dangerous gastrointestinal distress involving substantial loss of fluids (secretory diarrhea), among other issues. Most, if not all, of these signs are apparent at, or within a few months of, birth.Children with Levy-Yeboa syndrome appear to have blank expressions in their faces. This is due to the low tone of the muscles that normally reflect emotions..As of March 2014, three children of one family have been reliably diagnosed with LYS. A child in another family died before a definitive diagnosis could be made.
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Overview of Levy-Yeboa Syndrome. Levy-Yeboa syndrome (LYS) is a recently recognized, inherited (congenital), multi-system disorder involving signs of musculoskeletal involvement such as low muscle tone and stiffening of the joints of the arms and legs (contractions), loss of hearing (neuronal deafness), intense burn-like eruptions of the skin containing clear fluid (bullous eruptions) and dangerous gastrointestinal distress involving substantial loss of fluids (secretory diarrhea), among other issues. Most, if not all, of these signs are apparent at, or within a few months of, birth.Children with Levy-Yeboa syndrome appear to have blank expressions in their faces. This is due to the low tone of the muscles that normally reflect emotions..As of March 2014, three children of one family have been reliably diagnosed with LYS. A child in another family died before a definitive diagnosis could be made.
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Levy-Yeboa Syndrome
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Symptoms of Levy-Yeboa Syndrome
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MYOPATHY In the one family, a decrease in fetal movement was noted five weeks before delivery. Clinicians consider the decrease in fetal movement to be the earliest expression of the failure of muscle strength and tone (myopathy) that is so much a part of the syndrome. Further signs of the myopathy include contractures of the arms and legs joints, so that the limbs appear rigidly bent (sharp angulation). The elbows, wrists, hips, and ankles are mainly involved. In addition, the impassive, mask-like, expressionless face is considered to be another sign of the myopathy. NEUROSENSORY DEAFNESS Neurosensory deafness was confirmed in early infancy. DERMATOLOGY In LYS there are three primary symptoms involving the skin. These are: 1. Eruptions of fluid-filled blisters that resemble a skin disease known as epidermolysis bullosa simplex (EBS). These blisters were most obvious on the hands and feet, and cleared up in the first 3-6 months. 2. Generalized red (erythematous) rash, described as “fiery” and resembling first and second degree burns, occurs as a result of exposure to antibiotics and other drugs in the course of treatment. 3. Replacement of the red rash by intensely dark colored skin (hyperpigmentation) arising next to linear areas of low pigmentation (hypopigmentation) at the site of scars and punctures from hypodermic needles. SECRETORY DIARRHEA The loss of fluids with high sodium content that occurs as a result of secretory diarrhea may result in losses of more than one quart of fluid per day, even in the absence of any oral fluid intake. This is potentially lethal and probably the most dangerous clinical manifestation of LYS. This watery stool is easily overlooked since it may readily be mistaken for urine, delaying treatment with appropriate fluid replacement. Such diarrhea may present at any time from the first month to the sixth month of age, and tends to recur during intercurrent infections. The profuse diarrhea is believed to be responsible for the loss of important micronutrients, such as zinc, which in turn might play a role in the skin disorder. Indeed, skin biopsies suggested nutritional deficiencies and the skin condition improved with zinc replacement.
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Symptoms of Levy-Yeboa Syndrome. MYOPATHY In the one family, a decrease in fetal movement was noted five weeks before delivery. Clinicians consider the decrease in fetal movement to be the earliest expression of the failure of muscle strength and tone (myopathy) that is so much a part of the syndrome. Further signs of the myopathy include contractures of the arms and legs joints, so that the limbs appear rigidly bent (sharp angulation). The elbows, wrists, hips, and ankles are mainly involved. In addition, the impassive, mask-like, expressionless face is considered to be another sign of the myopathy. NEUROSENSORY DEAFNESS Neurosensory deafness was confirmed in early infancy. DERMATOLOGY In LYS there are three primary symptoms involving the skin. These are: 1. Eruptions of fluid-filled blisters that resemble a skin disease known as epidermolysis bullosa simplex (EBS). These blisters were most obvious on the hands and feet, and cleared up in the first 3-6 months. 2. Generalized red (erythematous) rash, described as “fiery” and resembling first and second degree burns, occurs as a result of exposure to antibiotics and other drugs in the course of treatment. 3. Replacement of the red rash by intensely dark colored skin (hyperpigmentation) arising next to linear areas of low pigmentation (hypopigmentation) at the site of scars and punctures from hypodermic needles. SECRETORY DIARRHEA The loss of fluids with high sodium content that occurs as a result of secretory diarrhea may result in losses of more than one quart of fluid per day, even in the absence of any oral fluid intake. This is potentially lethal and probably the most dangerous clinical manifestation of LYS. This watery stool is easily overlooked since it may readily be mistaken for urine, delaying treatment with appropriate fluid replacement. Such diarrhea may present at any time from the first month to the sixth month of age, and tends to recur during intercurrent infections. The profuse diarrhea is believed to be responsible for the loss of important micronutrients, such as zinc, which in turn might play a role in the skin disorder. Indeed, skin biopsies suggested nutritional deficiencies and the skin condition improved with zinc replacement.
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Causes of Levy-Yeboa Syndrome
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The cause of Levy-Yeboa syndrome remains unknown. Early in the investigation of LYS, it was thought that the disorder might be the result of defect(s) in the cell's factories for the synthesis and breakdown of energy-producing molecules, the mitochondria. The clinical researchers most familiar with the syndrome rule out mitochondrial defects as the source of the disorder as a result of muscle biopsies of tissue from brother, sisters, and metabolic blood screening of parents. These same clinicians suspected that the cause may be related to defects in the gene that controls the passages in the cell wall membrane through which potassium ions flow, the gene known as KCNQ. Defects in this gene could help to explain the gastrointestinal symptoms as well as the neurosensory deafness since such symptoms in other syndromes have been definitely linked to alterations in this gene. In addition, it is well known that mutations in the KCNQ1 and KCNE genes generate substantially different symptoms and signs in different people (pleiotropic effects). However, the relation of LYS to the KCNQ1 and KCNE3 genes was recently ruled out by linkage studies. Therefore, any of these conjectures remains “not proven” at this time.
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Causes of Levy-Yeboa Syndrome. The cause of Levy-Yeboa syndrome remains unknown. Early in the investigation of LYS, it was thought that the disorder might be the result of defect(s) in the cell's factories for the synthesis and breakdown of energy-producing molecules, the mitochondria. The clinical researchers most familiar with the syndrome rule out mitochondrial defects as the source of the disorder as a result of muscle biopsies of tissue from brother, sisters, and metabolic blood screening of parents. These same clinicians suspected that the cause may be related to defects in the gene that controls the passages in the cell wall membrane through which potassium ions flow, the gene known as KCNQ. Defects in this gene could help to explain the gastrointestinal symptoms as well as the neurosensory deafness since such symptoms in other syndromes have been definitely linked to alterations in this gene. In addition, it is well known that mutations in the KCNQ1 and KCNE genes generate substantially different symptoms and signs in different people (pleiotropic effects). However, the relation of LYS to the KCNQ1 and KCNE3 genes was recently ruled out by linkage studies. Therefore, any of these conjectures remains “not proven” at this time.
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Affects of Levy-Yeboa Syndrome
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There are too few instances or definitive cases of LYS to make any decisions regarding the incidence or prevalence of the disorder, or whether there are any biases regarding the sex of the child or ethnicity. As this syndrome becomes better and more widely known, more cases of LYS may be reported in the literature.
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Affects of Levy-Yeboa Syndrome. There are too few instances or definitive cases of LYS to make any decisions regarding the incidence or prevalence of the disorder, or whether there are any biases regarding the sex of the child or ethnicity. As this syndrome becomes better and more widely known, more cases of LYS may be reported in the literature.
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Related disorders of Levy-Yeboa Syndrome
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Symptoms of the following disorders can be similar to those of Levy-Yeboa syndrome. Comparisons may be useful for a differential diagnosis: Arthrogryposis multiplex congenita Arthrogryposis multiplex congenita, a rare disorder that is present at birth (congenital), is characterized by reduced mobility of many joints of the body. Impairment of mobility is due to the overgrowth (proliferation) of fibrous tissue in the joints (fibrous ankylosis). There are many different types of arthrogryposis multiplex congenita and the symptoms vary widely among affected individuals. In the most common form, the range of motion of the joints in the arms and legs (limbs) is limited or fixed. Other findings may include inward rotation of the shoulders, abnormal extension of the elbows, and bending of the wrists and fingers. In addition, the hips may be dislocated and the heels of the feet may be inwardly bent from the midline of the leg while the feet are inwardly bent at the ankle (clubfoot). The cause of arthrogryposis multiplex congenita (AMC) is unknown. Most types are not inherited; however, a rare autosomal recessive form of the disease has been reported in one large inbred Arabic kindred in Israel. Epidermolysis bullosa simplex Epidermolysis bullosa (EB) refers to a group of rare, inherited skin diseases characterized by recurring painful blisters and open sores, often in response to minor trauma, as a result of the unusually fragile nature of the skin. Some severe forms may involve the eyes, tongue, and esophagus, and some may produce scarring and disabling musculoskeletal deformities. There are three major forms: epidermolysis bullosa simplex (EB simplex), the most common; dystrophic epidermolysis bullosa (DEB), and junctional epidermolysis bullosa (JEB).
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Related disorders of Levy-Yeboa Syndrome. Symptoms of the following disorders can be similar to those of Levy-Yeboa syndrome. Comparisons may be useful for a differential diagnosis: Arthrogryposis multiplex congenita Arthrogryposis multiplex congenita, a rare disorder that is present at birth (congenital), is characterized by reduced mobility of many joints of the body. Impairment of mobility is due to the overgrowth (proliferation) of fibrous tissue in the joints (fibrous ankylosis). There are many different types of arthrogryposis multiplex congenita and the symptoms vary widely among affected individuals. In the most common form, the range of motion of the joints in the arms and legs (limbs) is limited or fixed. Other findings may include inward rotation of the shoulders, abnormal extension of the elbows, and bending of the wrists and fingers. In addition, the hips may be dislocated and the heels of the feet may be inwardly bent from the midline of the leg while the feet are inwardly bent at the ankle (clubfoot). The cause of arthrogryposis multiplex congenita (AMC) is unknown. Most types are not inherited; however, a rare autosomal recessive form of the disease has been reported in one large inbred Arabic kindred in Israel. Epidermolysis bullosa simplex Epidermolysis bullosa (EB) refers to a group of rare, inherited skin diseases characterized by recurring painful blisters and open sores, often in response to minor trauma, as a result of the unusually fragile nature of the skin. Some severe forms may involve the eyes, tongue, and esophagus, and some may produce scarring and disabling musculoskeletal deformities. There are three major forms: epidermolysis bullosa simplex (EB simplex), the most common; dystrophic epidermolysis bullosa (DEB), and junctional epidermolysis bullosa (JEB).
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Diagnosis of Levy-Yeboa Syndrome
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The diagnosis is based on the clinical picture presented in the child's first few weeks or months. A late decrease in fetal movement may be sufficient to raise suspicions or concerns regarding Levy-Yeboa syndrome. The combination of major symptoms, myopathy, deafness, skin eruptions and recurrent, massive, watery stools is definitive.
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Diagnosis of Levy-Yeboa Syndrome. The diagnosis is based on the clinical picture presented in the child's first few weeks or months. A late decrease in fetal movement may be sufficient to raise suspicions or concerns regarding Levy-Yeboa syndrome. The combination of major symptoms, myopathy, deafness, skin eruptions and recurrent, massive, watery stools is definitive.
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Therapies of Levy-Yeboa Syndrome
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TreatmentThe management of infants and children with LYS is demanding since so many different organ systems are affected and the patients are so young.Over time, intensive physical therapy may correct the deformities of the limbs. Also, there may be some improvement in the bland, blank facial expressions of the affected individual as he or she grows older.The burn-like skin symptoms require considerable attention at the site and systemically. Creams and other topical treatments used for the management of burns may ease the discomfort and minimize the chances of infection.The secretory (watery) diarrhea should be treated intermittently with intravenous nutrition for the first year of life. The bouts of diarrhea may ease after variable periods of time. In the opinion of the clinicians managing the cases diagnosed to date, the diarrhea appeared in some instances to be associated with infections that may or may not affect the digestive tract directly. Treatment with zinc supplements (oral 20mg/day zinc chloride for maintenance; intravenous 400-600 mcg/kg/day zinc as zinc sulphate during periods of worsening of the diarrhea) appeared to be effective.Hearing aids were of considerable help to the patients.The intellectual and verbal skills of those affected have appeared to be normal, and their musculoskeletal handicaps have improved over the years as a result of intensive physical, educational and speech therapy. The three children with this diagnosis attend regular school where they are active and social as they are at home. After age 2 years their rate of hospitalization has decreased significantly. Episodes of high fever that require intravenous (IV) management and close monitoring are the main reasons for in-patient hospitalization at this time. After age 4 years, several episodes of diarrhea were ended and managed with administration of Pedialyte, (a rehydration fluid) via a gastric tube or, if tolerated, by mouth. The intensity and frequency of the secretory diarrhea episodes tends to get better over time. However, when it reappears, management is challenging as stool volume losses are remarkable.Neither immunodeficiency nor opportunistic infections have been observed.
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Therapies of Levy-Yeboa Syndrome. TreatmentThe management of infants and children with LYS is demanding since so many different organ systems are affected and the patients are so young.Over time, intensive physical therapy may correct the deformities of the limbs. Also, there may be some improvement in the bland, blank facial expressions of the affected individual as he or she grows older.The burn-like skin symptoms require considerable attention at the site and systemically. Creams and other topical treatments used for the management of burns may ease the discomfort and minimize the chances of infection.The secretory (watery) diarrhea should be treated intermittently with intravenous nutrition for the first year of life. The bouts of diarrhea may ease after variable periods of time. In the opinion of the clinicians managing the cases diagnosed to date, the diarrhea appeared in some instances to be associated with infections that may or may not affect the digestive tract directly. Treatment with zinc supplements (oral 20mg/day zinc chloride for maintenance; intravenous 400-600 mcg/kg/day zinc as zinc sulphate during periods of worsening of the diarrhea) appeared to be effective.Hearing aids were of considerable help to the patients.The intellectual and verbal skills of those affected have appeared to be normal, and their musculoskeletal handicaps have improved over the years as a result of intensive physical, educational and speech therapy. The three children with this diagnosis attend regular school where they are active and social as they are at home. After age 2 years their rate of hospitalization has decreased significantly. Episodes of high fever that require intravenous (IV) management and close monitoring are the main reasons for in-patient hospitalization at this time. After age 4 years, several episodes of diarrhea were ended and managed with administration of Pedialyte, (a rehydration fluid) via a gastric tube or, if tolerated, by mouth. The intensity and frequency of the secretory diarrhea episodes tends to get better over time. However, when it reappears, management is challenging as stool volume losses are remarkable.Neither immunodeficiency nor opportunistic infections have been observed.
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Overview of Li-Fraumeni Syndrome
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SummaryLi-Fraumeni syndrome (LFS) is an inherited familial predisposition to a wide range of certain, often rare, cancers. This is due to a change (mutation) in a tumor suppressor gene known as TP53. The resulting p53 protein produced by the gene is damaged (or otherwise rendered malfunctioning) and is unable to help prevent malignant tumors from developing. Children and young adults are susceptible to developing several multiple cancers, most notably soft-tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinoma and acute leukemia. Other cancers seen in LFS patients include gastrointestinal cancers and cancers of the lung, kidney, thyroid, and skin, as well as in gonadal organs (ovarian, testicular, and prostate.)It is important to note that not everyone with a TP53 gene mutation will necessarily develop cancer, but the risks are substantially higher than in the general population. A diagnosis of LFS is critically important so that affected families can seek appropriate genetic counseling as well as surveillance for early detection of cancer.IntroductionLFS was first recognized in the 1969 by Drs. Frederick Li and Joseph Fraumeni, Jr., while studying pediatric and familial cancers at the National Cancer Institute. They described four families with multiple early-onset cancers in children and young adults. The syndrome was first reported in a publication as “Li-Fraumeni syndrome” in 1982 by researchers in the United Kingdom who described two families with multiple forms of cancer in young people.In 1990, inherited variants of the TP53 gene were discovered as the primary cause of LFS. This finding provided a special opportunity for genetic testing and clinical interventions that enable cancer prevention, early cancer detection, and cancer treatment of people with LFS. The finding also fueled further molecular research into TP53 which is commonly found in the tumor tissue of cancer patients.
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Overview of Li-Fraumeni Syndrome. SummaryLi-Fraumeni syndrome (LFS) is an inherited familial predisposition to a wide range of certain, often rare, cancers. This is due to a change (mutation) in a tumor suppressor gene known as TP53. The resulting p53 protein produced by the gene is damaged (or otherwise rendered malfunctioning) and is unable to help prevent malignant tumors from developing. Children and young adults are susceptible to developing several multiple cancers, most notably soft-tissue and bone sarcomas, breast cancer, brain tumors, adrenocortical carcinoma and acute leukemia. Other cancers seen in LFS patients include gastrointestinal cancers and cancers of the lung, kidney, thyroid, and skin, as well as in gonadal organs (ovarian, testicular, and prostate.)It is important to note that not everyone with a TP53 gene mutation will necessarily develop cancer, but the risks are substantially higher than in the general population. A diagnosis of LFS is critically important so that affected families can seek appropriate genetic counseling as well as surveillance for early detection of cancer.IntroductionLFS was first recognized in the 1969 by Drs. Frederick Li and Joseph Fraumeni, Jr., while studying pediatric and familial cancers at the National Cancer Institute. They described four families with multiple early-onset cancers in children and young adults. The syndrome was first reported in a publication as “Li-Fraumeni syndrome” in 1982 by researchers in the United Kingdom who described two families with multiple forms of cancer in young people.In 1990, inherited variants of the TP53 gene were discovered as the primary cause of LFS. This finding provided a special opportunity for genetic testing and clinical interventions that enable cancer prevention, early cancer detection, and cancer treatment of people with LFS. The finding also fueled further molecular research into TP53 which is commonly found in the tumor tissue of cancer patients.
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Symptoms of Li-Fraumeni Syndrome
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LFS may be suspected if someone has a personal or family history of cancers featured in LFS. In addition, there are certain rare cancers that are characteristic of the syndrome that should alert clinicians to the potential of a diagnosis of LFS. Patients and families with multiple childhood cancers, or specific rare cancers such as adrenocortical, choroid plexus carcinoma, anaplastic rhabdomyosarcoma, sonic hedgehog medulloblastoma, or hypodiploid acute lymphoblastic leukemia should alert practitioners to the potential of a hereditary cancer syndrome such as LFS. Although increasingly identified as a hereditary cancer syndrome, not all physicians are aware of the diagnosis of LFS.Cancers most closely associated (core cancers) with LFS include:• Soft tissue sarcoma
• Osteosarcoma
• Breast cancer
• Brain and CNS tumors (glioma, choroid plexus carcinoma, SHH subtype medulloblastoma, neuroblastoma)
• Adrenocortical carcinoma
• Acute leukemiaOther cancers may also appear, but risks are lower than for the core cancers:• Lung adenocarcinoma
• Melanoma
• Gastrointestinal tumors (such as colon, pancreas)
• Kidney
• Thyroid
• Gonadal germ cells (such as ovarian, testicular, and prostate)Individuals with LFS have an approximately 50% of developing cancer by age 40, and up to a 90% percent chance by age 60, while females have nearly a 100% risk of developing cancer in their lifetime due to their markedly increased risk of breast cancer. Many individuals with LFS develop two or more primary cancers over their lifetimes.
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Symptoms of Li-Fraumeni Syndrome. LFS may be suspected if someone has a personal or family history of cancers featured in LFS. In addition, there are certain rare cancers that are characteristic of the syndrome that should alert clinicians to the potential of a diagnosis of LFS. Patients and families with multiple childhood cancers, or specific rare cancers such as adrenocortical, choroid plexus carcinoma, anaplastic rhabdomyosarcoma, sonic hedgehog medulloblastoma, or hypodiploid acute lymphoblastic leukemia should alert practitioners to the potential of a hereditary cancer syndrome such as LFS. Although increasingly identified as a hereditary cancer syndrome, not all physicians are aware of the diagnosis of LFS.Cancers most closely associated (core cancers) with LFS include:• Soft tissue sarcoma
• Osteosarcoma
• Breast cancer
• Brain and CNS tumors (glioma, choroid plexus carcinoma, SHH subtype medulloblastoma, neuroblastoma)
• Adrenocortical carcinoma
• Acute leukemiaOther cancers may also appear, but risks are lower than for the core cancers:• Lung adenocarcinoma
• Melanoma
• Gastrointestinal tumors (such as colon, pancreas)
• Kidney
• Thyroid
• Gonadal germ cells (such as ovarian, testicular, and prostate)Individuals with LFS have an approximately 50% of developing cancer by age 40, and up to a 90% percent chance by age 60, while females have nearly a 100% risk of developing cancer in their lifetime due to their markedly increased risk of breast cancer. Many individuals with LFS develop two or more primary cancers over their lifetimes.
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Li-Fraumeni Syndrome
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Causes of Li-Fraumeni Syndrome
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Li-Fraumeni syndrome is caused by an inherited (germline) pathogenic variant of the TP53 tumor suppressor gene on chromosome 17. LFS was first recognized in 1969, and in 1979, TP53 was identified in the tumor tissue of more than 50% of all cancer patients. However, it wasn’t until 1990 that a TP53 germline variant was discovered to be the cause of LFS.LFS follows autosomal dominant inheritance. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent and can result from a new mutation (gene change) in the affected individual. The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Most people with LFS have a germline TP53 gene mutation, but in some individuals, LFS is due to a spontaneous (de novo) genetic variant that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.There are many known variations of malfunctioning TP53, and each can affect every person in a family differently. Most families with LFS have very high cancer incidence rates, while some others do not, and even within families, the aggressiveness of the syndrome varies. The degree to which a TP53 variant causes cancer in a family or individual is called “penetrance.”Individuals with LFS may also be prone to the carcinogenic risks associated with certain lifestyle or environmental exposures, such as tobacco smoking or radiation exposure. LFS patients should take preventive measures to reduce their exposures to behavioral risk factors and carcinogens.
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Causes of Li-Fraumeni Syndrome. Li-Fraumeni syndrome is caused by an inherited (germline) pathogenic variant of the TP53 tumor suppressor gene on chromosome 17. LFS was first recognized in 1969, and in 1979, TP53 was identified in the tumor tissue of more than 50% of all cancer patients. However, it wasn’t until 1990 that a TP53 germline variant was discovered to be the cause of LFS.LFS follows autosomal dominant inheritance. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an altered gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent and can result from a new mutation (gene change) in the affected individual. The risk of passing the altered gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.Most people with LFS have a germline TP53 gene mutation, but in some individuals, LFS is due to a spontaneous (de novo) genetic variant that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.There are many known variations of malfunctioning TP53, and each can affect every person in a family differently. Most families with LFS have very high cancer incidence rates, while some others do not, and even within families, the aggressiveness of the syndrome varies. The degree to which a TP53 variant causes cancer in a family or individual is called “penetrance.”Individuals with LFS may also be prone to the carcinogenic risks associated with certain lifestyle or environmental exposures, such as tobacco smoking or radiation exposure. LFS patients should take preventive measures to reduce their exposures to behavioral risk factors and carcinogens.
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Affects of Li-Fraumeni Syndrome
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Though it is challenging to estimate to frequency in the population, there are likely over 1,000 multigenerational families worldwide with LFS. To date, inquiries on the LFS Association website have arrived from 172 countries.There is no evidence of ethnic or geographic disparity in the occurrence of LFS, but a uniquely high prevalence of LFS has been reported in southern and southeastern Brazil. The population with LFS in this area has been associated with a highly specific variant of the TP53 referred to as R337H. Having this particular alteration in the region led researchers to suspect one point of origin, and family lineages were traced to a common ancestor who migrated long ago from Portugal. Interestingly, though, as opposed to the 90% lifetime risk of developing cancer in most people with LFS, the population in Brazil with this “founder mutation” has roughly a 60% lifetime risk of cancers, which have relatively favorable survival rates.
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Affects of Li-Fraumeni Syndrome. Though it is challenging to estimate to frequency in the population, there are likely over 1,000 multigenerational families worldwide with LFS. To date, inquiries on the LFS Association website have arrived from 172 countries.There is no evidence of ethnic or geographic disparity in the occurrence of LFS, but a uniquely high prevalence of LFS has been reported in southern and southeastern Brazil. The population with LFS in this area has been associated with a highly specific variant of the TP53 referred to as R337H. Having this particular alteration in the region led researchers to suspect one point of origin, and family lineages were traced to a common ancestor who migrated long ago from Portugal. Interestingly, though, as opposed to the 90% lifetime risk of developing cancer in most people with LFS, the population in Brazil with this “founder mutation” has roughly a 60% lifetime risk of cancers, which have relatively favorable survival rates.
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Related disorders of Li-Fraumeni Syndrome
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There are several other conditions with an increased cancer risk not related to variants of TP53.
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Related disorders of Li-Fraumeni Syndrome. There are several other conditions with an increased cancer risk not related to variants of TP53.
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Diagnosis of Li-Fraumeni Syndrome
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Li-Fraumeni syndrome is diagnosed based on the presence of a so called pathogenic or likely pathogenic variant in the TP53 gene. Genetic TP53 testing is typically considered with the below delineated criteria.Clinical Testing (Clinical Screening & Genetic Testing)The potential of genetic testing (and the implications of the results) should always involve discussions with a genetic counselor, medical providers and family.As delineated by the American Society of Clinical Oncology, the below criteria can be used in determining if genetic testing should be considered:Classic LFS is diagnosed when a person has all of the following criteria:• A sarcoma diagnosed before age 45• A first-degree relative, meaning a parent, sibling or child, with any cancer before age 45• A first-degree relative or second-degree relative, meaning a grandparent, aunt/uncle, niece/nephew, or grandchild, with any cancer before age 45 or a sarcoma at any ageChompret Criteria for Clinical Diagnosis of Li-Fraumeni Syndrome is a recent set of criteria that has been proposed to identify affected families beyond the Classic criteria listed above. A diagnosis of LFS and performing TP53 gene mutation testing is considered for anyone with a personal and family history that meets 1 of the following 3 criteria:Criterion 1• A tumor belonging to the LFS tumor spectrum, before the age of 46. This means any of the following diseases: soft-tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumor, adrenal cortical carcinoma, leukemia, or lung cancer, and• At least 1 first-degree or second-degree family member with an LFS-related tumor, except breast cancer if the individual has breast cancer before the age of 56 or with multiple tumorsCriterion 2• A person with multiple tumors, except multiple breast tumors, 2 of which belonging to the LFS tumor spectrum and the first of which occurred before age 46Criterion 3• A person who is diagnosed with adrenocortical carcinoma or a tumor in the choroid plexus, meaning a membrane around the brain, regardless of family history.In addition, patients with anaplastic rhabdomyosarcoma, women with breast cancer prior to age 31 years, patients with hypodiploid acute lymphoblastic leukemia and SHH medulloblastoma should be tested, regardless of family history. Li-Fraumeni-Like Syndrome (LFL) is another, similar set of criteria for affected families who do not meet Classic criteria (see above). There are 2 suggested definitions for LFL:LFL Definition 1, called the Birch definition:• A person diagnosed with any childhood cancer, sarcoma, brain tumor, or adrenal cortical tumor before age 45 and• A first-degree or second-degree relative diagnosed with a typical LFS cancer, such as sarcoma, breast cancer, brain cancer, adrenal cortical tumor, or leukemia, at any age and• A first-degree or second-degree relative diagnosed with any cancer before age 60LFL Definition 2, called the Eeles definition:• 2 first-degree or second-degree relatives diagnosed with a typical LFS cancer, such as sarcoma, breast cancer, brain cancer, adrenal cortical tumor, or leukemia, at any ageOther risk factors to consider, specific to breast cancer:A woman who has a personal history of breast cancer at a younger age and does not have an identifiable mutation in breast cancer genes 1 or 2, called BRCA1 or BRCA2, may have a TP53 mutation.A woman who is diagnosed with breast cancer before age 30 and is not found to have a BRCA mutation has an estimated 4% to 8% likelihood of having a TP53 mutation.Women with breast cancer diagnosed between ages 30 and 39 may also have a small increased risk of having a TP53 mutation.In younger woman with breast cancer, a TP53 mutation may also occur with any of the following features: a family history of cancer, especially LFS-related cancers, a personal history of a breast tumor that is positive for estrogen (ER), progesterone (PR), and HER2/neu markers, also known as “triple-positive” breast cancer, and a personal history of an additional LFS-related cancer.
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Diagnosis of Li-Fraumeni Syndrome. Li-Fraumeni syndrome is diagnosed based on the presence of a so called pathogenic or likely pathogenic variant in the TP53 gene. Genetic TP53 testing is typically considered with the below delineated criteria.Clinical Testing (Clinical Screening & Genetic Testing)The potential of genetic testing (and the implications of the results) should always involve discussions with a genetic counselor, medical providers and family.As delineated by the American Society of Clinical Oncology, the below criteria can be used in determining if genetic testing should be considered:Classic LFS is diagnosed when a person has all of the following criteria:• A sarcoma diagnosed before age 45• A first-degree relative, meaning a parent, sibling or child, with any cancer before age 45• A first-degree relative or second-degree relative, meaning a grandparent, aunt/uncle, niece/nephew, or grandchild, with any cancer before age 45 or a sarcoma at any ageChompret Criteria for Clinical Diagnosis of Li-Fraumeni Syndrome is a recent set of criteria that has been proposed to identify affected families beyond the Classic criteria listed above. A diagnosis of LFS and performing TP53 gene mutation testing is considered for anyone with a personal and family history that meets 1 of the following 3 criteria:Criterion 1• A tumor belonging to the LFS tumor spectrum, before the age of 46. This means any of the following diseases: soft-tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumor, adrenal cortical carcinoma, leukemia, or lung cancer, and• At least 1 first-degree or second-degree family member with an LFS-related tumor, except breast cancer if the individual has breast cancer before the age of 56 or with multiple tumorsCriterion 2• A person with multiple tumors, except multiple breast tumors, 2 of which belonging to the LFS tumor spectrum and the first of which occurred before age 46Criterion 3• A person who is diagnosed with adrenocortical carcinoma or a tumor in the choroid plexus, meaning a membrane around the brain, regardless of family history.In addition, patients with anaplastic rhabdomyosarcoma, women with breast cancer prior to age 31 years, patients with hypodiploid acute lymphoblastic leukemia and SHH medulloblastoma should be tested, regardless of family history. Li-Fraumeni-Like Syndrome (LFL) is another, similar set of criteria for affected families who do not meet Classic criteria (see above). There are 2 suggested definitions for LFL:LFL Definition 1, called the Birch definition:• A person diagnosed with any childhood cancer, sarcoma, brain tumor, or adrenal cortical tumor before age 45 and• A first-degree or second-degree relative diagnosed with a typical LFS cancer, such as sarcoma, breast cancer, brain cancer, adrenal cortical tumor, or leukemia, at any age and• A first-degree or second-degree relative diagnosed with any cancer before age 60LFL Definition 2, called the Eeles definition:• 2 first-degree or second-degree relatives diagnosed with a typical LFS cancer, such as sarcoma, breast cancer, brain cancer, adrenal cortical tumor, or leukemia, at any ageOther risk factors to consider, specific to breast cancer:A woman who has a personal history of breast cancer at a younger age and does not have an identifiable mutation in breast cancer genes 1 or 2, called BRCA1 or BRCA2, may have a TP53 mutation.A woman who is diagnosed with breast cancer before age 30 and is not found to have a BRCA mutation has an estimated 4% to 8% likelihood of having a TP53 mutation.Women with breast cancer diagnosed between ages 30 and 39 may also have a small increased risk of having a TP53 mutation.In younger woman with breast cancer, a TP53 mutation may also occur with any of the following features: a family history of cancer, especially LFS-related cancers, a personal history of a breast tumor that is positive for estrogen (ER), progesterone (PR), and HER2/neu markers, also known as “triple-positive” breast cancer, and a personal history of an additional LFS-related cancer.
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Li-Fraumeni Syndrome
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Therapies of Li-Fraumeni Syndrome
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Treatment
At this time, there is no standard treatment or cure for LFS or a germline TP53 gene variant. With some exceptions, cancers in people with LFS are treated the same as for cancers in other patients, but research continues on how to best manage those cancers involved in LFS.Research has indicated that those individuals with LFS appear to be an elevated risk for radiation-induced cancers, so the use of radiotherapy should be approached with caution. For this reason, computed tomography (CT) scans and other diagnostic techniques involving ionizing radiation should be limited. However, radiation therapy should not be avoided if the benefits outweigh the risks.Since those living with LFS are susceptible to the development of a number of different cancers, individuals should ensure that they incorporate simple measures into a healthy lifestyle, such as sun protection and the avoidance of tobacco products.It has been widely accepted that early cancer detection can greatly increase overall survival, and those diagnosed with LFS should seek to adhere to preventive screening. An expert panel of LFS researchers, oncologists, and genetic counselors has published surveillance recommendations that utilize whole body MRI screening for patients with LFS. This should be offered as soon as the diagnosis of LFS is established. In brief, the screening recommendations involve:Children (birth to age 18 years)
• General assessment
o Complete physical exam every 3-4 months
o Prompt assessment with primary care physician for any medical concerns• Adrenocortical carcinoma
o Ultrasound of abdomen and pelvis every 3-4 months
o In case of unsatisfactory ultrasound, blood tests every 3-4 months• Brain tumor
o Annual brain MRI (first MRI with contrast – thereafter without contrast if previous MRI normal with and no new abnormality• Soft tissue and bone sarcoma
o Annual whole body MRIAdults
• General assessment
o Complete physical exam every 6 months
o Prompt assessment with primary care physician for any medical concerns• Breast cancer
o Breast awareness (age 18 years and forward)
o Clinical breast exam twice a year (age 20 years and forward)
o Annual breast MRI screening (ages 20-75) – ideally, alternating with annual whole body MRI (one scan every 6 months)
o Consider risk-reducing bilateral mastectomy (Note that the use of ultrasound and mammography has been omitted)• Brain tumor (age 18 years and forward)
o Annual brain MRI (first MRI with contrast – thereafter without contrast if previous MRI normal)• Soft tissue and bone sarcoma (age 18 years and forward)
o Annual whole body MRI
o Ultrasound of abdomen and pelvis every 12 months• Gastrointestinal cancer (age 25 years and forward)
o Upper endoscopy and colonoscopy every 2-5 years)• Melanoma (age 18 years and forward)
o Annual dermatologic examinationAlso noted, for families in which breast cancer has already made an appearance at or around age 20 – awareness and screening can be considered 5 to 10 years before the earliest age of onset known. The same is recommended for gastrointestinal cancers – consider screening 5 years before the earliest known onset of a gastrointestinal cancer in the family.See Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome (June 2017) for more information. (https://www.lfsassociation.org/wp-content/uploads/2017/06/e38.full_.pdf)
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Therapies of Li-Fraumeni Syndrome. Treatment
At this time, there is no standard treatment or cure for LFS or a germline TP53 gene variant. With some exceptions, cancers in people with LFS are treated the same as for cancers in other patients, but research continues on how to best manage those cancers involved in LFS.Research has indicated that those individuals with LFS appear to be an elevated risk for radiation-induced cancers, so the use of radiotherapy should be approached with caution. For this reason, computed tomography (CT) scans and other diagnostic techniques involving ionizing radiation should be limited. However, radiation therapy should not be avoided if the benefits outweigh the risks.Since those living with LFS are susceptible to the development of a number of different cancers, individuals should ensure that they incorporate simple measures into a healthy lifestyle, such as sun protection and the avoidance of tobacco products.It has been widely accepted that early cancer detection can greatly increase overall survival, and those diagnosed with LFS should seek to adhere to preventive screening. An expert panel of LFS researchers, oncologists, and genetic counselors has published surveillance recommendations that utilize whole body MRI screening for patients with LFS. This should be offered as soon as the diagnosis of LFS is established. In brief, the screening recommendations involve:Children (birth to age 18 years)
• General assessment
o Complete physical exam every 3-4 months
o Prompt assessment with primary care physician for any medical concerns• Adrenocortical carcinoma
o Ultrasound of abdomen and pelvis every 3-4 months
o In case of unsatisfactory ultrasound, blood tests every 3-4 months• Brain tumor
o Annual brain MRI (first MRI with contrast – thereafter without contrast if previous MRI normal with and no new abnormality• Soft tissue and bone sarcoma
o Annual whole body MRIAdults
• General assessment
o Complete physical exam every 6 months
o Prompt assessment with primary care physician for any medical concerns• Breast cancer
o Breast awareness (age 18 years and forward)
o Clinical breast exam twice a year (age 20 years and forward)
o Annual breast MRI screening (ages 20-75) – ideally, alternating with annual whole body MRI (one scan every 6 months)
o Consider risk-reducing bilateral mastectomy (Note that the use of ultrasound and mammography has been omitted)• Brain tumor (age 18 years and forward)
o Annual brain MRI (first MRI with contrast – thereafter without contrast if previous MRI normal)• Soft tissue and bone sarcoma (age 18 years and forward)
o Annual whole body MRI
o Ultrasound of abdomen and pelvis every 12 months• Gastrointestinal cancer (age 25 years and forward)
o Upper endoscopy and colonoscopy every 2-5 years)• Melanoma (age 18 years and forward)
o Annual dermatologic examinationAlso noted, for families in which breast cancer has already made an appearance at or around age 20 – awareness and screening can be considered 5 to 10 years before the earliest age of onset known. The same is recommended for gastrointestinal cancers – consider screening 5 years before the earliest known onset of a gastrointestinal cancer in the family.See Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome (June 2017) for more information. (https://www.lfsassociation.org/wp-content/uploads/2017/06/e38.full_.pdf)
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Overview of Lichen Planus
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Lichen planus (LP) is a rare, chronic, inflammatory autoimmune skin and mucous membrane disease. LP most commonly presents as itchy, shiny, reddish-purple spots (lesions) on the skin (cutaneous LP) or as white-gray lesions in the mouth or on the lips (oral LP). Less commonly, LP may also involve the genitals (penile or vulvar LP), scalp (lichen planopilaris), ears (otic LP), nails, eyes, and esophagus. Similar to lichen found growing on trees and rocks in forests, the skin lesions are often flat-topped and can be somewhat scaly, hence the name “lichen” planus.
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Overview of Lichen Planus. Lichen planus (LP) is a rare, chronic, inflammatory autoimmune skin and mucous membrane disease. LP most commonly presents as itchy, shiny, reddish-purple spots (lesions) on the skin (cutaneous LP) or as white-gray lesions in the mouth or on the lips (oral LP). Less commonly, LP may also involve the genitals (penile or vulvar LP), scalp (lichen planopilaris), ears (otic LP), nails, eyes, and esophagus. Similar to lichen found growing on trees and rocks in forests, the skin lesions are often flat-topped and can be somewhat scaly, hence the name “lichen” planus.
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Lichen Planus
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Symptoms of Lichen Planus
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weeks or months and intermittent recurrences may occur for years. The appearance of the lesions is dependent on their location. In cutaneous LP, the lesions can present anywhere on the skin, usually on the wrists, legs, palms and soles or torso and are 2 to 4 mm in diameter with angular borders, a violet color and a distinct sheen in cross-lighting. These lesions tend to be symmetrically distributed and may also coalesce into rough scaly patches. Rarely, blisters may develop. Moderate to severe itching is common and frequently fails to respond to treatment.There are several variants of cutaneous LP, which may present differently. The lesions may become large, scaly and warty (hypertrophic LP), particularly on the lower legs. New spots may appear along a site of minor skin injury such as a superficial scratch (Koebner’s phenomenon). Sometimes degeneration (atrophy) of the skin may occur as lesions persist (atrophic LP) and some patients experience an absence of sweating due to degeneration of sweat glands (anhidrosis).In areas where lesions have healed, an unusual darkening (hyperpigmentation) or lightening (hypopigmentation) of the skin may occur.Between 50 and 70 percent of patients show symptoms involving “mucous membranes”, the moist pink skin that lines the inside of the mouth, vagina, and esophagus. LP on mucous membranes can present as red, painful sores, or lesions that have a net-like, white pattern. Oral symptoms often occur before skin lesions develop. Oral symptoms, consisting of a dryness and metallic taste or burning in the mouth, may appear first and may be the only evidence of the disease.Although not common, hair loss may be among the consequences of LP, which is called lichen planopilaris. When and if hair loss does occur, it can involve small patchy areas of the scalp (atrophic cictrical alopecia) or cause a receding hairline (frontal fibrosing alopecia). Due to scarring, this hair loss is permanent if untreated. For more information on lichen planopilaris, visit https://rarediseases.info.nih.gov/diseases/3247/lichen-planopilaris.Nail LP presents in 10 to 25 percent of LP patients and tends to present as roughness, vertical ridges or cracks, and thinning of the nail. This can eventually lead to scarring of the nail.Trouble swallowing, or pain with swallowing can indicate esophageal LP. It is important to treat esophageal disease, as it can eventually lead to the esophagus narrowing over time, called esophageal stricture.Some cases of cutaneous LP will resolve with time, while oral, genital, nail, and esophageal LP are more persistent and may increase in severity over time. Patients with LP are at an increased risk of squamous cell carcinoma, particularly of the oral mucosa, and need to be monitored periodically.
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Symptoms of Lichen Planus. weeks or months and intermittent recurrences may occur for years. The appearance of the lesions is dependent on their location. In cutaneous LP, the lesions can present anywhere on the skin, usually on the wrists, legs, palms and soles or torso and are 2 to 4 mm in diameter with angular borders, a violet color and a distinct sheen in cross-lighting. These lesions tend to be symmetrically distributed and may also coalesce into rough scaly patches. Rarely, blisters may develop. Moderate to severe itching is common and frequently fails to respond to treatment.There are several variants of cutaneous LP, which may present differently. The lesions may become large, scaly and warty (hypertrophic LP), particularly on the lower legs. New spots may appear along a site of minor skin injury such as a superficial scratch (Koebner’s phenomenon). Sometimes degeneration (atrophy) of the skin may occur as lesions persist (atrophic LP) and some patients experience an absence of sweating due to degeneration of sweat glands (anhidrosis).In areas where lesions have healed, an unusual darkening (hyperpigmentation) or lightening (hypopigmentation) of the skin may occur.Between 50 and 70 percent of patients show symptoms involving “mucous membranes”, the moist pink skin that lines the inside of the mouth, vagina, and esophagus. LP on mucous membranes can present as red, painful sores, or lesions that have a net-like, white pattern. Oral symptoms often occur before skin lesions develop. Oral symptoms, consisting of a dryness and metallic taste or burning in the mouth, may appear first and may be the only evidence of the disease.Although not common, hair loss may be among the consequences of LP, which is called lichen planopilaris. When and if hair loss does occur, it can involve small patchy areas of the scalp (atrophic cictrical alopecia) or cause a receding hairline (frontal fibrosing alopecia). Due to scarring, this hair loss is permanent if untreated. For more information on lichen planopilaris, visit https://rarediseases.info.nih.gov/diseases/3247/lichen-planopilaris.Nail LP presents in 10 to 25 percent of LP patients and tends to present as roughness, vertical ridges or cracks, and thinning of the nail. This can eventually lead to scarring of the nail.Trouble swallowing, or pain with swallowing can indicate esophageal LP. It is important to treat esophageal disease, as it can eventually lead to the esophagus narrowing over time, called esophageal stricture.Some cases of cutaneous LP will resolve with time, while oral, genital, nail, and esophageal LP are more persistent and may increase in severity over time. Patients with LP are at an increased risk of squamous cell carcinoma, particularly of the oral mucosa, and need to be monitored periodically.
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Lichen Planus
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Causes of Lichen Planus
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In most affected individuals, the exact cause of LP is unclear. It is suspected that exposure to infections, drugs, allergens, or injury may sensitize the immune system and cause the immune system to attack skin cells. This initial eruption may persist for weeks to months, and recurrences can continue throughout the individual’s lifetime. There have been reports of LP in family members, indicating that there may be a genetic predisposition, but the genetic factors of LP are still being researched and are uncertain.
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Causes of Lichen Planus. In most affected individuals, the exact cause of LP is unclear. It is suspected that exposure to infections, drugs, allergens, or injury may sensitize the immune system and cause the immune system to attack skin cells. This initial eruption may persist for weeks to months, and recurrences can continue throughout the individual’s lifetime. There have been reports of LP in family members, indicating that there may be a genetic predisposition, but the genetic factors of LP are still being researched and are uncertain.
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Lichen Planus
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Affects of Lichen Planus
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There is limited data on how many people are affected by LP, but most studies estimate that LP occurs in less than 1 percent of the world’s population. Cutaneous LP occurs at similar frequencies in men and women, but women are somewhat more likely to develop oral LP or lichen planopilaris. There does not appear to be a racial predisposition for the disease. The majority of LP develops between 30 and 60 years of age but can affect older and younger individuals as well. In rare cases, children may be affected.
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Affects of Lichen Planus. There is limited data on how many people are affected by LP, but most studies estimate that LP occurs in less than 1 percent of the world’s population. Cutaneous LP occurs at similar frequencies in men and women, but women are somewhat more likely to develop oral LP or lichen planopilaris. There does not appear to be a racial predisposition for the disease. The majority of LP develops between 30 and 60 years of age but can affect older and younger individuals as well. In rare cases, children may be affected.
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Lichen Planus
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Related disorders of Lichen Planus
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There are several diseases that can look very similar to LP and are important to differentiate.Some metals such as gold salts, arsenic, bismuth, cinnamon (cinnamic aldehyde), or exposure to certain chemicals, may cause an eruption indistinguishable from LP, either oral or cutaneous. When a patient has symptoms of LP, physicians will likely ask about medication history because multiple medications have been associated with a drug-induced LP including antimalarials (hydroxychloroquine, quinacrine and chloroquine), blood pressure medications, proton pump inhibitors, some antibiotics, TNF inhibitors, NSAIDS (such as ibuprofen), and many others. If the eruption is due to exposure to metals, chemicals, or drugs, symptoms usually resolve a few weeks to months after eliminating the exposure but may still recur intermittently over time.Candida species are normally harmless yeasts found in the mouth, intestinal tract, and vagina. Candidiasis (also known as a yeast infection or thrush) may occur when an imbalance is created in the host’s body and usually affects the skin and/or the mucous membranes of the mouth, intestines, or the vagina. Oral candidiasis can look similar to oral LP, with white patches in the mouth. Candida infections are rarely serious in otherwise healthy people. In people with oral LP, superficial Candida infections may also occur in combination with LP, especially in people using topical steroids. (For more information on this disorder, choose “Candidiasis” as your search term in the Rare Disease Database.)Other skin conditions that can be confused with cutaneous LP are psoriasis, syphilis, graft versus host disease, lupus affecting the skin, erythema multiforme, and erythema dischromicum perstans (ashy dermatosis). Oral LP needs to be distinguished from other erosive mucosal conditions such as pemphigus, pemphigoid, and recurrent apthous ulcers (canker sores). These conditions can be differentiated from LP through clinical evaluation, blood tests, and biopsies.
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Related disorders of Lichen Planus. There are several diseases that can look very similar to LP and are important to differentiate.Some metals such as gold salts, arsenic, bismuth, cinnamon (cinnamic aldehyde), or exposure to certain chemicals, may cause an eruption indistinguishable from LP, either oral or cutaneous. When a patient has symptoms of LP, physicians will likely ask about medication history because multiple medications have been associated with a drug-induced LP including antimalarials (hydroxychloroquine, quinacrine and chloroquine), blood pressure medications, proton pump inhibitors, some antibiotics, TNF inhibitors, NSAIDS (such as ibuprofen), and many others. If the eruption is due to exposure to metals, chemicals, or drugs, symptoms usually resolve a few weeks to months after eliminating the exposure but may still recur intermittently over time.Candida species are normally harmless yeasts found in the mouth, intestinal tract, and vagina. Candidiasis (also known as a yeast infection or thrush) may occur when an imbalance is created in the host’s body and usually affects the skin and/or the mucous membranes of the mouth, intestines, or the vagina. Oral candidiasis can look similar to oral LP, with white patches in the mouth. Candida infections are rarely serious in otherwise healthy people. In people with oral LP, superficial Candida infections may also occur in combination with LP, especially in people using topical steroids. (For more information on this disorder, choose “Candidiasis” as your search term in the Rare Disease Database.)Other skin conditions that can be confused with cutaneous LP are psoriasis, syphilis, graft versus host disease, lupus affecting the skin, erythema multiforme, and erythema dischromicum perstans (ashy dermatosis). Oral LP needs to be distinguished from other erosive mucosal conditions such as pemphigus, pemphigoid, and recurrent apthous ulcers (canker sores). These conditions can be differentiated from LP through clinical evaluation, blood tests, and biopsies.
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Lichen Planus
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Diagnosis of Lichen Planus
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A diagnosis of LP can often be made from an examination of the skin or mucous membranes and identification of the characteristic clinical features. Clinical Testing and Work-Up
If a diagnosis is not clear based on clinical findings, it is common for the physician to take a small sample of skin (biopsy) to confirm the diagnosis.
There is some evidence of an association between LP (especially with oral LP) and hepatitis C virus infection and blood testing may be ordered by your physician. In cases where an allergy is suspected, a type of allergy test called patch testing may be helpful to identify the cause.
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Diagnosis of Lichen Planus. A diagnosis of LP can often be made from an examination of the skin or mucous membranes and identification of the characteristic clinical features. Clinical Testing and Work-Up
If a diagnosis is not clear based on clinical findings, it is common for the physician to take a small sample of skin (biopsy) to confirm the diagnosis.
There is some evidence of an association between LP (especially with oral LP) and hepatitis C virus infection and blood testing may be ordered by your physician. In cases where an allergy is suspected, a type of allergy test called patch testing may be helpful to identify the cause.
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Lichen Planus
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Therapies of Lichen Planus
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Treatment
In mild cases, symptoms may be minimal or absent and no therapy may be needed. For patients requiring treatment, first line therapy is usually a topical corticosteroid medication. These are available in many strengths and formulations including cream, ointment, gels, solutions, oral rinses and others. If topical corticosteroids are not effective or cause side effects, a non-steroid topical medication called tacrolimus or pimecrolimus may be prescribed.Erosive oral lesions and widespread itchy skin lesions often require the use of a systemic corticosteroid (e.g., oral prednisone). Unfortunately, skin lesions may return after systemic prednisone has been discontinued. In this case, continued low dosage of a systemic corticosteroid may be instituted.Phototherapy may be helpful for widespread skin disease. In more severe refractory cases, stronger immune suppressing medications may be needed such as mycophenolate mofetil, methotrexate, azathioprine, cyclosporine, and others.
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Therapies of Lichen Planus. Treatment
In mild cases, symptoms may be minimal or absent and no therapy may be needed. For patients requiring treatment, first line therapy is usually a topical corticosteroid medication. These are available in many strengths and formulations including cream, ointment, gels, solutions, oral rinses and others. If topical corticosteroids are not effective or cause side effects, a non-steroid topical medication called tacrolimus or pimecrolimus may be prescribed.Erosive oral lesions and widespread itchy skin lesions often require the use of a systemic corticosteroid (e.g., oral prednisone). Unfortunately, skin lesions may return after systemic prednisone has been discontinued. In this case, continued low dosage of a systemic corticosteroid may be instituted.Phototherapy may be helpful for widespread skin disease. In more severe refractory cases, stronger immune suppressing medications may be needed such as mycophenolate mofetil, methotrexate, azathioprine, cyclosporine, and others.
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Lichen Planus
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Overview of Lichen Sclerosus
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Lichen sclerosus is a chronic inflammatory skin disorder that most commonly affects women before puberty or after menopause. Although rare, it can also be seen in men. When found in males, the disease is known as balanitis xerotica obliterans.Lichen sclerosus is characterized by skin changes of the external genitalia. The most common distribution is a figure of 8 involving the vulva and perianal area. The head of the penis and other parts of the body may also be affected. In fact, this skin condition can affect any skin surface. Some patients with lichen sclerosus do not have any symptoms, whereas others experience intense itching, discomfort and/or erosions/ulcers. Lichen sclerosus typically has a remitting relapsing course that is complicated by permanent scarring of the affected areas. This produces functional problems such as difficulty in urination, defecation, and intercourse for affected women and difficulty in urination or with erections in men. The disorder is not contagious nor is it a sexually transmitted disease.Current research supports that it is caused by a combination of a dysfunction of the immunological system and genetic factors. The understanding of the causes of this disorder is still incomplete. The mainstay of treatment is potent topical steroids in the case of genital involvement in women. Studies have shown that regular use of potent topical steroids in women prevents the problems of scarring and decreases risk of skin cancer developing in the area of lichen sclerosus. Potent topical steroids are also a first line treatment for other areas affected by lichen sclerosus. Pelvic floor therapy, surgical intervention to address scarring (such as circumcision in men), and in some cases oral immunosuppressive medicines may also be used. Because lichen sclerosus is associated with increased risk of squamous cell carcinoma in women with genital involvement, it is important for those affected to have life long screening examinations as well as continued treatment to keep the disorder under control.
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Overview of Lichen Sclerosus. Lichen sclerosus is a chronic inflammatory skin disorder that most commonly affects women before puberty or after menopause. Although rare, it can also be seen in men. When found in males, the disease is known as balanitis xerotica obliterans.Lichen sclerosus is characterized by skin changes of the external genitalia. The most common distribution is a figure of 8 involving the vulva and perianal area. The head of the penis and other parts of the body may also be affected. In fact, this skin condition can affect any skin surface. Some patients with lichen sclerosus do not have any symptoms, whereas others experience intense itching, discomfort and/or erosions/ulcers. Lichen sclerosus typically has a remitting relapsing course that is complicated by permanent scarring of the affected areas. This produces functional problems such as difficulty in urination, defecation, and intercourse for affected women and difficulty in urination or with erections in men. The disorder is not contagious nor is it a sexually transmitted disease.Current research supports that it is caused by a combination of a dysfunction of the immunological system and genetic factors. The understanding of the causes of this disorder is still incomplete. The mainstay of treatment is potent topical steroids in the case of genital involvement in women. Studies have shown that regular use of potent topical steroids in women prevents the problems of scarring and decreases risk of skin cancer developing in the area of lichen sclerosus. Potent topical steroids are also a first line treatment for other areas affected by lichen sclerosus. Pelvic floor therapy, surgical intervention to address scarring (such as circumcision in men), and in some cases oral immunosuppressive medicines may also be used. Because lichen sclerosus is associated with increased risk of squamous cell carcinoma in women with genital involvement, it is important for those affected to have life long screening examinations as well as continued treatment to keep the disorder under control.
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Lichen Sclerosus
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Symptoms of Lichen Sclerosus
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Lichen sclerosus usually affects the external genitalia (vulva or penis) and/or the area around the anus (perianal region). Sometimes, it is accompanied by intense (intractable) itching, burning, and pain. If the disease is severe, even minor abrasions or chaffing can cause bleeding, tearing, and blistering. The scarring that results from untreated lichen sclerosus produces problems with urination, defecation, and intercourse. The presence of thin, easily irritated, and torn skin affects physical activity and clothing choice.For children with lichen sclerosus affecting the perianal region, constipation may be among the first signs of the presence of the disease. Lichen sclerosus is much more likely to affect males that have not been circumcised than males that have been.Rarely, lichen sclerosus can also affect other areas of the skin such as the breast, wrists, shoulder, neck, back, thigh, and the mouth.Skin tissue often becomes thin, shiny, wrinkled and parchment-like. Fissures, cracks, and purplish patches (ecchymoses) appear frequently. The earliest areas of lichen sclerosus exhibit a porcelain white appearing center surrounded by redness. This grows together to form larger areas of lichen sclerosus. The areas that are prone to rubbing and friction can develop blisters or bruising. The long term result of lichen sclerosus are areas of shiny, thin skin that has a tendency to be dry, crack, or bleed. This also produces loss of the normal parts of the external genitals, narrowing of the opening of the urerthra/vagina/anus, and phimosis (inability to retract the foreskin) in men. The presence of non-healing ulcers or raised ulcerated areas in the external genitalia of women raises suspicion for the development of squamous cell carcinoma.In males, lichen sclerosus most commonly affects the foreskin of the penis, although it may affect other areas of the body. The opening at the end of the foreskin may become narrow and scarred. Discoloration and skin changes may also occur. Symptoms also include itching, soreness, and painful erections. In men, involvement in the perineal area is rare.In some rare cases, skin lesions may also develop in the mouth. The lesions consist of bluish-white flat irregular patchy areas on the inside of the cheeks and/or palate. The tongue, lips, and gums may also be involved.
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Symptoms of Lichen Sclerosus. Lichen sclerosus usually affects the external genitalia (vulva or penis) and/or the area around the anus (perianal region). Sometimes, it is accompanied by intense (intractable) itching, burning, and pain. If the disease is severe, even minor abrasions or chaffing can cause bleeding, tearing, and blistering. The scarring that results from untreated lichen sclerosus produces problems with urination, defecation, and intercourse. The presence of thin, easily irritated, and torn skin affects physical activity and clothing choice.For children with lichen sclerosus affecting the perianal region, constipation may be among the first signs of the presence of the disease. Lichen sclerosus is much more likely to affect males that have not been circumcised than males that have been.Rarely, lichen sclerosus can also affect other areas of the skin such as the breast, wrists, shoulder, neck, back, thigh, and the mouth.Skin tissue often becomes thin, shiny, wrinkled and parchment-like. Fissures, cracks, and purplish patches (ecchymoses) appear frequently. The earliest areas of lichen sclerosus exhibit a porcelain white appearing center surrounded by redness. This grows together to form larger areas of lichen sclerosus. The areas that are prone to rubbing and friction can develop blisters or bruising. The long term result of lichen sclerosus are areas of shiny, thin skin that has a tendency to be dry, crack, or bleed. This also produces loss of the normal parts of the external genitals, narrowing of the opening of the urerthra/vagina/anus, and phimosis (inability to retract the foreskin) in men. The presence of non-healing ulcers or raised ulcerated areas in the external genitalia of women raises suspicion for the development of squamous cell carcinoma.In males, lichen sclerosus most commonly affects the foreskin of the penis, although it may affect other areas of the body. The opening at the end of the foreskin may become narrow and scarred. Discoloration and skin changes may also occur. Symptoms also include itching, soreness, and painful erections. In men, involvement in the perineal area is rare.In some rare cases, skin lesions may also develop in the mouth. The lesions consist of bluish-white flat irregular patchy areas on the inside of the cheeks and/or palate. The tongue, lips, and gums may also be involved.
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Causes of Lichen Sclerosus
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The exact cause of lichen sclerosus is not known. Most research indicates it is an autoimmune condition. Autoimmune disorders arise when the body’s natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. Some cases of lichen sclerosus may be linked to formation of certain antibodies (e.g. a thyroid protein (thyroglobulin), or certain cells that line the walls of organs).Some scientists believe that a genetic predisposition to lichen sclerosus exists. A genetic predisposition means that a person may carry a gene for a disease but it may not be expressed unless something in the environment triggers the disease. Other researchers believe that hormonal, irritant and/or infectious factors (or a combination of these) cause this skin condition. Cases where lichen sclerosus appears on skin after it has been damaged (from an injury or trauma) have been reported.Recent research suggests that the most probable cause of lichen sclerosus is an autoimmune reaction in genetically predisposed individuals.
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Causes of Lichen Sclerosus. The exact cause of lichen sclerosus is not known. Most research indicates it is an autoimmune condition. Autoimmune disorders arise when the body’s natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. Some cases of lichen sclerosus may be linked to formation of certain antibodies (e.g. a thyroid protein (thyroglobulin), or certain cells that line the walls of organs).Some scientists believe that a genetic predisposition to lichen sclerosus exists. A genetic predisposition means that a person may carry a gene for a disease but it may not be expressed unless something in the environment triggers the disease. Other researchers believe that hormonal, irritant and/or infectious factors (or a combination of these) cause this skin condition. Cases where lichen sclerosus appears on skin after it has been damaged (from an injury or trauma) have been reported.Recent research suggests that the most probable cause of lichen sclerosus is an autoimmune reaction in genetically predisposed individuals.
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Affects of Lichen Sclerosus
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Lichen sclerosus affects mostly females, usually between the ages of 40 and 60 years. Females are six times as likely to be affected as are males. Younger females and males have also been identified in the medical literature in the United States. Female children under the age of thirteen have also been reported with the condition.
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Affects of Lichen Sclerosus. Lichen sclerosus affects mostly females, usually between the ages of 40 and 60 years. Females are six times as likely to be affected as are males. Younger females and males have also been identified in the medical literature in the United States. Female children under the age of thirteen have also been reported with the condition.
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Related disorders of Lichen Sclerosus
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Symptoms of the following disorders can be similar to those of lichen sclerosus. Comparisons may be useful for a differential diagnosis:Morphea or localized scleroderma occurs in adults and children. Recent studies indicate that up to 20% of those with morphea, particularly post-menopausal women, may have changes that resemble lichen sclerosus in the genital area. Moreover, lesions of morphea may co-exist with lichen sclerosus on the body. For this reason, those with lichen sclerosus should have their skin examined for signs of morphea and those with morphea should be checked for lichen sclerosus.Lichen planus is a rare disorder associated with recurrent, itchy, inflammatory eruptions of the skin. Which are usually small separate, angular spots that may merge into rough scaly patches. Lichen planus is often accompanied by lesions in the mouth. Females are most commonly affected by the disorder. (For more information on this disorder, choose “lichen planus” as your search term in the Rare Disease Database.)Carcinoma of the vulva is a malignant disease characterized by abnormal cancerous changes in the skin of the vulva. Changes can resemble those of severe lichen sclerosus.Hyperplastic dystrophy of vulva represents an skin response to injury and is usually accompanied by itching. It may be caused by ingestion of foods with high acid content or contact with a chemical such as a laundry detergent, body soap, hygiene sprays, dye in toilet paper, or other various substances that come in contact with the skin. Some fabrics or unusually tight clothing may cause this condition. In some cases, there may be no apparent cause. Corticosteroid cream often clears up the skin symptoms. This medication may be used as a continued maintenance treatment in patients who experience recurring symptoms.Lichen simplex chronicus represents skin changes around the vulva that are related to chronic irritation. It is characterized by thick plaques of skin that are usually red and itchy.
Endogenous and exogenous dermatitis is an inflammatory skin condition. It can present as an itchy red rash. More advanced forms of the condition can have skin thickening and fissures. A biopsy may be required to differentiate dermatitis from early lichen sclerosus.Vitiligo can have a similar presentation as lichen sclerosus that has few symptoms. It produces bilateral symmetric whitening of the skin. Sometimes vitiligo and lichen sclerosus can be present in the same person.Skin conditions that can look like lichen sclorosus in areas of the body other than the genital area include tinea versicolor (a fungal infection), anetoderma, cutaneous T-cell lymphoma, chronic graft versus host disease (in patients who have received organ or cell transplants), and squamous cell carcinoma.
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Related disorders of Lichen Sclerosus. Symptoms of the following disorders can be similar to those of lichen sclerosus. Comparisons may be useful for a differential diagnosis:Morphea or localized scleroderma occurs in adults and children. Recent studies indicate that up to 20% of those with morphea, particularly post-menopausal women, may have changes that resemble lichen sclerosus in the genital area. Moreover, lesions of morphea may co-exist with lichen sclerosus on the body. For this reason, those with lichen sclerosus should have their skin examined for signs of morphea and those with morphea should be checked for lichen sclerosus.Lichen planus is a rare disorder associated with recurrent, itchy, inflammatory eruptions of the skin. Which are usually small separate, angular spots that may merge into rough scaly patches. Lichen planus is often accompanied by lesions in the mouth. Females are most commonly affected by the disorder. (For more information on this disorder, choose “lichen planus” as your search term in the Rare Disease Database.)Carcinoma of the vulva is a malignant disease characterized by abnormal cancerous changes in the skin of the vulva. Changes can resemble those of severe lichen sclerosus.Hyperplastic dystrophy of vulva represents an skin response to injury and is usually accompanied by itching. It may be caused by ingestion of foods with high acid content or contact with a chemical such as a laundry detergent, body soap, hygiene sprays, dye in toilet paper, or other various substances that come in contact with the skin. Some fabrics or unusually tight clothing may cause this condition. In some cases, there may be no apparent cause. Corticosteroid cream often clears up the skin symptoms. This medication may be used as a continued maintenance treatment in patients who experience recurring symptoms.Lichen simplex chronicus represents skin changes around the vulva that are related to chronic irritation. It is characterized by thick plaques of skin that are usually red and itchy.
Endogenous and exogenous dermatitis is an inflammatory skin condition. It can present as an itchy red rash. More advanced forms of the condition can have skin thickening and fissures. A biopsy may be required to differentiate dermatitis from early lichen sclerosus.Vitiligo can have a similar presentation as lichen sclerosus that has few symptoms. It produces bilateral symmetric whitening of the skin. Sometimes vitiligo and lichen sclerosus can be present in the same person.Skin conditions that can look like lichen sclorosus in areas of the body other than the genital area include tinea versicolor (a fungal infection), anetoderma, cutaneous T-cell lymphoma, chronic graft versus host disease (in patients who have received organ or cell transplants), and squamous cell carcinoma.
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Diagnosis of Lichen Sclerosus
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Lichen sclerosus is diagnosed by looking at the skin affected. All those affected require a thorough clinical evaluation, identification of characteristic physical features, and a detailed patient history. There should be focus on the functional impact of the lichen sclerosus and treatment to date, including over the counter products that might be applied. In order to be sure of the diagnosis, a skin biopsy may be needed. Biopsies may also be performed if squamous cell carcinoma is suspected.
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Diagnosis of Lichen Sclerosus. Lichen sclerosus is diagnosed by looking at the skin affected. All those affected require a thorough clinical evaluation, identification of characteristic physical features, and a detailed patient history. There should be focus on the functional impact of the lichen sclerosus and treatment to date, including over the counter products that might be applied. In order to be sure of the diagnosis, a skin biopsy may be needed. Biopsies may also be performed if squamous cell carcinoma is suspected.
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Therapies of Lichen Sclerosus
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Treatment
Vulvar lichen sclerosus requires aggressive treatment and life long monitoring to avert scarring and minimize risk of squamous cell carcinoma. Treatment consists of the use of one or another of the ultrapotent corticosteroids that are available by prescription, and should be used as an ointment (use of creams is discouraged). Ultrapotent corticosteroids available in the United States include: betamethasone diproprionate, clobetasol propionate, diflorasone diacetate, and halobetasol propionate. These drugs may stop the itching within days or a couple of weeks. Within a few months of regular use, they may make it possible for skin to regain its strength and texture, but they cannot affect scarring or changes in skin color that may already have taken place. Current recommendations are to use the steroid ointment twice a day for several weeks until in remission and then taper down to a long term maintenance regimen with use of the steroid ointment a few times a week. Patients’ providers should give them detailed instructions on where to apply the ointment and how to apply it. Often, photos are taken to help track improvement and monitor for change. It is critical for women to have life long follow up with a provider familiar with lichen sclerosus for ongoing monitoring of treatment and surveillance for squamous cell carcinoma.Treatment in men is not well studied. In those who are not circumcised, circumcision can be curative. Otherwise, potent topical steroid ointments are also recommended. The same is true of extragenital lesions. The link with squamous cell carcinoma has not been demonstrated in men or in extragenital lesions, so long term follow-up is recommended mainly to maintain control of the lichen sclerosus, but the risk of cancer appears to be very low in men.
Second line treatments include topical tacrolimus or pimecrolimus, phototherapy, and systemic (oral) immunosuppressive medications. In very severe cases, surgical removal of affected skin layers may be of benefit. In males, circumcision may be helpful (if the foreskin is involved). It is usually reserved for individuals who have scarring that causes functional impairment.For lichen sclerosus that is not located in the genital area, potent topical corticosteroids are the first-line treatment. Other options include phototherapy, systemic steroids, and rarely, systemic immunosuppressive therapy.
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Therapies of Lichen Sclerosus. Treatment
Vulvar lichen sclerosus requires aggressive treatment and life long monitoring to avert scarring and minimize risk of squamous cell carcinoma. Treatment consists of the use of one or another of the ultrapotent corticosteroids that are available by prescription, and should be used as an ointment (use of creams is discouraged). Ultrapotent corticosteroids available in the United States include: betamethasone diproprionate, clobetasol propionate, diflorasone diacetate, and halobetasol propionate. These drugs may stop the itching within days or a couple of weeks. Within a few months of regular use, they may make it possible for skin to regain its strength and texture, but they cannot affect scarring or changes in skin color that may already have taken place. Current recommendations are to use the steroid ointment twice a day for several weeks until in remission and then taper down to a long term maintenance regimen with use of the steroid ointment a few times a week. Patients’ providers should give them detailed instructions on where to apply the ointment and how to apply it. Often, photos are taken to help track improvement and monitor for change. It is critical for women to have life long follow up with a provider familiar with lichen sclerosus for ongoing monitoring of treatment and surveillance for squamous cell carcinoma.Treatment in men is not well studied. In those who are not circumcised, circumcision can be curative. Otherwise, potent topical steroid ointments are also recommended. The same is true of extragenital lesions. The link with squamous cell carcinoma has not been demonstrated in men or in extragenital lesions, so long term follow-up is recommended mainly to maintain control of the lichen sclerosus, but the risk of cancer appears to be very low in men.
Second line treatments include topical tacrolimus or pimecrolimus, phototherapy, and systemic (oral) immunosuppressive medications. In very severe cases, surgical removal of affected skin layers may be of benefit. In males, circumcision may be helpful (if the foreskin is involved). It is usually reserved for individuals who have scarring that causes functional impairment.For lichen sclerosus that is not located in the genital area, potent topical corticosteroids are the first-line treatment. Other options include phototherapy, systemic steroids, and rarely, systemic immunosuppressive therapy.
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Overview of Liddle Syndrome
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Summary Liddle syndrome is a rare genetic disorder caused by abnormal kidney function that results in high blood pressure (hypertension). This disorder is caused by a disease-causing variant (mutation) in one of 3 genes (SCNN1A, SCNN1B, and SCNN1G) that encode the epithelial sodium channel (ENaC).While ENaC is present throughout the body in organs such as the lungs and kidney, ENaC activity in the kidney characterizes the clinical presentation. Mutation of one of the 3 genes that cause Liddle syndrome results in higher-than-normal ENaC activity. Over-active ENaC in the distal nephrons of the kidney leads to excessive sodium reabsorption and associated electrolyte imbalances. The excess sodium retention effects blood pressure control, resulting in hypertension that is resistant to most anti-hypertensive medications. Potassium secretion in the kidney is affected, and low concentration of serum blood potassium (hypokalemia) is present in most, but not all, patients.Plasma renin activity and serum aldosterone levels are low. Severity of hypertension, which is the presenting finding, varies from mild to severe, even in patients in the same family. The symptoms and severity can vary by age, sex and life events such as pregnancy. Amiloride, a potassium-sparing diuretic, inhibits ENaC, and is the mainstay of therapy. Additional treatment includes a low-salt diet and additional anti-hypertensive medications, as needed.Introduction Liddle syndrome is a monogenic cause of hypertension, meaning that a mutation in just one gene (either SCNN1A, SCNN1B, or SCNN1G) is sufficient to cause hypertension. Other single gene mutations resulting in hypertension (including familial hyperkalemic hypertension, glucocorticoid remedial aldosteronism, apparent mineralocorticoid excess, and activating mineralocorticoid receptor mutation) also cause hypertension by increasing sodium reabsorption in the kidney. Monogenetic hypertensions are remarkable because most cases of hypertension have no single, identifiable cause and are termed “essential” or “primary” hypertension. While monogenic hypertension disorders are rare, their scientific impact in the understanding of hypertension has been immense. They have led to the identification of the kidney’s role in the pathophysiology of hypertension as well as the importance of dietary salt in hypertension management. Liddle syndrome is sometimes grouped with other disease processes affecting renal tubules, known as “tubulopathies,” including the subtypes of renal tubular acidosis (proximal, distal, and hyperkalemic) and nephrogenic diabetes insipidus. It is also sometimes discussed with other “channelopathies”, or disorders caused by the dysfunction of an ion channel, or regulation of an ion channel (Kim 2014). Ion channels are proteins which facilitate the movement of inorganic ions such as Ca2+, K+, Mg2+, or Na+ across cell membranes. Liddle syndrome is also sometimes grouped as a form of pseudohyperaldosteronism, or conditions that present with similar symptoms to hyperaldosteronism (such as elevated blood pressure, hypokalemia, metabolic acidosis and low levels of plasma renin activity) in the absence of elevated aldosterone. Other kinds of pseudohyperaldosteronism can be caused by mutations to 11-beta-hydroxysteroid dehyrdrogenase type 2 gene, which is responsible for lowering cortisol levels in aldosterone sensitive principal cells of the nephron, congenital overproduction of 11-deoxycorticosterone, tumors, or natural licorice consumption. The identification of Liddle syndrome as an autosomal dominant, monogenetic renal tubulopathy of the ENaC was driven by the work of Dr. Grant Liddle, the efforts of “GS”‘ the first reported patient, and the pioneering work of Drs. David Warnock, Richard Lifton, Bernard Rossier, Richard Shimkets and Mauricio Botero-Velez. Dr. Warnock has called GS, the patient ‘sparkplug,' who enabled the charting of the first Liddle syndrome pedigree.In 1960, Dr. Liddle examined a 16-year-old female (GS) who had been referred to him with a diagnosis of aldosteronism, producing negligible amounts of aldosterone and high levels of sodium in her bloodstream and saliva. In 1963, Liddle wrote the results of her treatment, as well as his treatment of her younger brother. Liddle concluded that the siblings, “had an unusual tendency to conserve sodium and excrete potassium, even in the virtual absence of mineralocorticoids (Liddle and GW 1963). He administered triamterene, an inhibitor of ENaC and designed a low sodium diet. In his article, Dr. Liddle also presented a survey of 23 family members, noting that their mother and maternal grandmother had both died in their forties of hypertensive vascular disease, but no such issues were identified in the father’s family. Liddle hypothesized that this pseudo-aldosteronism was a familial renal disorder.In 1989, GS, 43 years old, was admitted to the University of Alabama at Birmingham (UAB) Medical Center to receive a cadaver kidney transplant. Most fascinating was that the transplanted kidney had “normalized” her ability to process sodium, “curing” her symptoms. Interest in Dr. Liddle’s work was reignited when she identified herself to UAB researchers as the patient described in his 1963 article.GS facilitated the expansion of her lineage to 43, the results confirming the hypothesis of a familial disorder. The specimens were provided for genetic analysis, to the Howard Hughes Medical lnstitute, Lifton Laboratory at Yale University. The analysis, combined with four other subject specimens, identified the linkage of symptoms with a subunit of the kidney ENaC, the three genes that cause Liddle syndrome. GS lived to learn of the genetic identification, the fruition of Dr. Liddle’s familial renal disorder hypothesis.
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Overview of Liddle Syndrome. Summary Liddle syndrome is a rare genetic disorder caused by abnormal kidney function that results in high blood pressure (hypertension). This disorder is caused by a disease-causing variant (mutation) in one of 3 genes (SCNN1A, SCNN1B, and SCNN1G) that encode the epithelial sodium channel (ENaC).While ENaC is present throughout the body in organs such as the lungs and kidney, ENaC activity in the kidney characterizes the clinical presentation. Mutation of one of the 3 genes that cause Liddle syndrome results in higher-than-normal ENaC activity. Over-active ENaC in the distal nephrons of the kidney leads to excessive sodium reabsorption and associated electrolyte imbalances. The excess sodium retention effects blood pressure control, resulting in hypertension that is resistant to most anti-hypertensive medications. Potassium secretion in the kidney is affected, and low concentration of serum blood potassium (hypokalemia) is present in most, but not all, patients.Plasma renin activity and serum aldosterone levels are low. Severity of hypertension, which is the presenting finding, varies from mild to severe, even in patients in the same family. The symptoms and severity can vary by age, sex and life events such as pregnancy. Amiloride, a potassium-sparing diuretic, inhibits ENaC, and is the mainstay of therapy. Additional treatment includes a low-salt diet and additional anti-hypertensive medications, as needed.Introduction Liddle syndrome is a monogenic cause of hypertension, meaning that a mutation in just one gene (either SCNN1A, SCNN1B, or SCNN1G) is sufficient to cause hypertension. Other single gene mutations resulting in hypertension (including familial hyperkalemic hypertension, glucocorticoid remedial aldosteronism, apparent mineralocorticoid excess, and activating mineralocorticoid receptor mutation) also cause hypertension by increasing sodium reabsorption in the kidney. Monogenetic hypertensions are remarkable because most cases of hypertension have no single, identifiable cause and are termed “essential” or “primary” hypertension. While monogenic hypertension disorders are rare, their scientific impact in the understanding of hypertension has been immense. They have led to the identification of the kidney’s role in the pathophysiology of hypertension as well as the importance of dietary salt in hypertension management. Liddle syndrome is sometimes grouped with other disease processes affecting renal tubules, known as “tubulopathies,” including the subtypes of renal tubular acidosis (proximal, distal, and hyperkalemic) and nephrogenic diabetes insipidus. It is also sometimes discussed with other “channelopathies”, or disorders caused by the dysfunction of an ion channel, or regulation of an ion channel (Kim 2014). Ion channels are proteins which facilitate the movement of inorganic ions such as Ca2+, K+, Mg2+, or Na+ across cell membranes. Liddle syndrome is also sometimes grouped as a form of pseudohyperaldosteronism, or conditions that present with similar symptoms to hyperaldosteronism (such as elevated blood pressure, hypokalemia, metabolic acidosis and low levels of plasma renin activity) in the absence of elevated aldosterone. Other kinds of pseudohyperaldosteronism can be caused by mutations to 11-beta-hydroxysteroid dehyrdrogenase type 2 gene, which is responsible for lowering cortisol levels in aldosterone sensitive principal cells of the nephron, congenital overproduction of 11-deoxycorticosterone, tumors, or natural licorice consumption. The identification of Liddle syndrome as an autosomal dominant, monogenetic renal tubulopathy of the ENaC was driven by the work of Dr. Grant Liddle, the efforts of “GS”‘ the first reported patient, and the pioneering work of Drs. David Warnock, Richard Lifton, Bernard Rossier, Richard Shimkets and Mauricio Botero-Velez. Dr. Warnock has called GS, the patient ‘sparkplug,' who enabled the charting of the first Liddle syndrome pedigree.In 1960, Dr. Liddle examined a 16-year-old female (GS) who had been referred to him with a diagnosis of aldosteronism, producing negligible amounts of aldosterone and high levels of sodium in her bloodstream and saliva. In 1963, Liddle wrote the results of her treatment, as well as his treatment of her younger brother. Liddle concluded that the siblings, “had an unusual tendency to conserve sodium and excrete potassium, even in the virtual absence of mineralocorticoids (Liddle and GW 1963). He administered triamterene, an inhibitor of ENaC and designed a low sodium diet. In his article, Dr. Liddle also presented a survey of 23 family members, noting that their mother and maternal grandmother had both died in their forties of hypertensive vascular disease, but no such issues were identified in the father’s family. Liddle hypothesized that this pseudo-aldosteronism was a familial renal disorder.In 1989, GS, 43 years old, was admitted to the University of Alabama at Birmingham (UAB) Medical Center to receive a cadaver kidney transplant. Most fascinating was that the transplanted kidney had “normalized” her ability to process sodium, “curing” her symptoms. Interest in Dr. Liddle’s work was reignited when she identified herself to UAB researchers as the patient described in his 1963 article.GS facilitated the expansion of her lineage to 43, the results confirming the hypothesis of a familial disorder. The specimens were provided for genetic analysis, to the Howard Hughes Medical lnstitute, Lifton Laboratory at Yale University. The analysis, combined with four other subject specimens, identified the linkage of symptoms with a subunit of the kidney ENaC, the three genes that cause Liddle syndrome. GS lived to learn of the genetic identification, the fruition of Dr. Liddle’s familial renal disorder hypothesis.
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Symptoms of Liddle Syndrome
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There is no overt set of symptoms that is distinct in persons with Liddle syndrome to uniquely distinguish it from other disorders. The lack of an easily observable set of traits in the patient's physical examination, other than an elevated blood pressure reading, presents difficulties for diagnosis (see sections below on Diagnosis and Related Disorders).The most notable finding in those with a Liddle syndrome mutation is a high risk of developing hypertension (high blood pressure). Hypertension is estimated to affect about 92% of people with a disease-causing mutation for Liddle syndrome (Tetti et al. 2018). Many Liddle syndrome patients have been observed to develop hypertension at an unusually early age, often in the teenage years (Cui et al. 2017). Resistant hypertension in children and teenagers may alert the clinician to consider tests for Liddle syndrome. The degree of hypertension in patients with Liddle syndrome is variable, as are the downstream effects of hypertension such as damage to other organs caused by high blood pressure. Typical clinical findings include hypokalemia (low potassium in the blood), hypertension, metabolic alkalosis (high pH in the blood) and low plasma aldosterone and renin activity. Each of these findings is variable, for example, hypokalemia is not found universally among Liddle syndrome patients. The reabsorption of sodium from overactive ENaC in the kidney facilitates a loss of potassium and protons in the urine, causing both hypokalemia and metabolic alkalosis. These findings are similar to patients with an excess of aldosterone, since upregulating ENaC is an important action of aldosterone in the kidney. However, in Liddle syndrome ENaC is highly active in the absence of aldosterone. In the salt-expanded state caused by Liddle syndrome, the renin-angiotensin-aldosterone cascade is downregulated or suppressed, resulting in both low plasma renin activity and low serum aldosterone levels.
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Symptoms of Liddle Syndrome. There is no overt set of symptoms that is distinct in persons with Liddle syndrome to uniquely distinguish it from other disorders. The lack of an easily observable set of traits in the patient's physical examination, other than an elevated blood pressure reading, presents difficulties for diagnosis (see sections below on Diagnosis and Related Disorders).The most notable finding in those with a Liddle syndrome mutation is a high risk of developing hypertension (high blood pressure). Hypertension is estimated to affect about 92% of people with a disease-causing mutation for Liddle syndrome (Tetti et al. 2018). Many Liddle syndrome patients have been observed to develop hypertension at an unusually early age, often in the teenage years (Cui et al. 2017). Resistant hypertension in children and teenagers may alert the clinician to consider tests for Liddle syndrome. The degree of hypertension in patients with Liddle syndrome is variable, as are the downstream effects of hypertension such as damage to other organs caused by high blood pressure. Typical clinical findings include hypokalemia (low potassium in the blood), hypertension, metabolic alkalosis (high pH in the blood) and low plasma aldosterone and renin activity. Each of these findings is variable, for example, hypokalemia is not found universally among Liddle syndrome patients. The reabsorption of sodium from overactive ENaC in the kidney facilitates a loss of potassium and protons in the urine, causing both hypokalemia and metabolic alkalosis. These findings are similar to patients with an excess of aldosterone, since upregulating ENaC is an important action of aldosterone in the kidney. However, in Liddle syndrome ENaC is highly active in the absence of aldosterone. In the salt-expanded state caused by Liddle syndrome, the renin-angiotensin-aldosterone cascade is downregulated or suppressed, resulting in both low plasma renin activity and low serum aldosterone levels.
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Causes of Liddle Syndrome
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Liddle syndrome is an autosomal dominant genetic disorder caused by mutations in the genes that code for the epithelial sodium channel (SCNN1A, SCNN1B, and SCNN1G). These mutations result in an increase in ENaC activity, sodium and water retention and hypertension. The epithelial sodium channel (ENaC) is an ion channel. Each channel is composed of three subunits, alpha, beta, and gamma (each subunit transcribed from a separate gene: SCNN1A, SCNN1B, and SCNN1G, respectively). Each of these subunits spans the cellular membrane at both ends and has a large extracellular loop. ENaC is expressed on the surface of many cells including epithelial cells of the lung, skin, colon, reproductive tracts, brain and kidney. Most relevant to Liddle syndrome is ENaC function in kidney principal cells, where ENaC facilitates movement of sodium from filtrate into the cell. A balance of insertion and removal of ENaCs in the cell membrane is one of many factors that influence ENaC activity. In Liddle syndrome, retrieval of ENaC from the cell membrane is impaired, resulting in an over-abundance of ENaC and therefore an overall increase in activity. Mutations identified in SCCN1A, SCNN1B and SCNN1G genes alter the retrieval and degradation of these subunits from the cellular membrane by preventing a process known as ubiquitination, which tags subunits for retrieval from the membrane. Most Liddle syndrome cases identified to date have been caused by mutations to SCNN1B or SCNN1G. However, a family with Liddle syndrome caused by an SCNN1A mutation has been identified recently (Salih, 2017).The recovery of sodium and water from the kidney back to blood are linked and are a regulator of the plasma volume. Most of the sodium and water is recovered with little regulation early in nephrons, the units in the kidney that process plasma and produce urine. The last, and regulated, step in recovery of sodium, involves ENaC. The high activity of ENaC in patients with Liddle syndrome results in more sodium reabsorption and a salt-expanded state. The relative excess of salt in the body causes the blood pressure to increase due to the linked increase in plasma volume.The principal cells in the kidney, where ENaC reabsorbs sodium, have multiple functions. One of these functions is to secrete potassium. When sodium ions are removed from the filtrate, potassium and hydrogen ions move into the urine, balancing charge. Overtime, the loss of potassium and protons in the urine can lead to hypokalemia (low potassium in the blood) and metabolic alkalosis (elevated pH in the blood), respectively.Liddle syndrome is inherited in an autosomal dominant manner, so it is likely to occur in multiple members of the same family. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
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Causes of Liddle Syndrome. Liddle syndrome is an autosomal dominant genetic disorder caused by mutations in the genes that code for the epithelial sodium channel (SCNN1A, SCNN1B, and SCNN1G). These mutations result in an increase in ENaC activity, sodium and water retention and hypertension. The epithelial sodium channel (ENaC) is an ion channel. Each channel is composed of three subunits, alpha, beta, and gamma (each subunit transcribed from a separate gene: SCNN1A, SCNN1B, and SCNN1G, respectively). Each of these subunits spans the cellular membrane at both ends and has a large extracellular loop. ENaC is expressed on the surface of many cells including epithelial cells of the lung, skin, colon, reproductive tracts, brain and kidney. Most relevant to Liddle syndrome is ENaC function in kidney principal cells, where ENaC facilitates movement of sodium from filtrate into the cell. A balance of insertion and removal of ENaCs in the cell membrane is one of many factors that influence ENaC activity. In Liddle syndrome, retrieval of ENaC from the cell membrane is impaired, resulting in an over-abundance of ENaC and therefore an overall increase in activity. Mutations identified in SCCN1A, SCNN1B and SCNN1G genes alter the retrieval and degradation of these subunits from the cellular membrane by preventing a process known as ubiquitination, which tags subunits for retrieval from the membrane. Most Liddle syndrome cases identified to date have been caused by mutations to SCNN1B or SCNN1G. However, a family with Liddle syndrome caused by an SCNN1A mutation has been identified recently (Salih, 2017).The recovery of sodium and water from the kidney back to blood are linked and are a regulator of the plasma volume. Most of the sodium and water is recovered with little regulation early in nephrons, the units in the kidney that process plasma and produce urine. The last, and regulated, step in recovery of sodium, involves ENaC. The high activity of ENaC in patients with Liddle syndrome results in more sodium reabsorption and a salt-expanded state. The relative excess of salt in the body causes the blood pressure to increase due to the linked increase in plasma volume.The principal cells in the kidney, where ENaC reabsorbs sodium, have multiple functions. One of these functions is to secrete potassium. When sodium ions are removed from the filtrate, potassium and hydrogen ions move into the urine, balancing charge. Overtime, the loss of potassium and protons in the urine can lead to hypokalemia (low potassium in the blood) and metabolic alkalosis (elevated pH in the blood), respectively.Liddle syndrome is inherited in an autosomal dominant manner, so it is likely to occur in multiple members of the same family. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
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Affects of Liddle Syndrome
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Estimates of how common Liddle syndrome is vary. A survey of symptoms of veteran patients with hypertension found that 6% met the non-genetic diagnostic criteria for Liddle syndrome (Tapolyai et al. 2010), which is a much higher prevalence than confirmed cases by genetic testing. Gene sequencing studies of early onset hypertension have suggested a population prevalence of about 0.9–1.5% among those who develop hypertension before age 30 (Liu et al. 2018). While most confirmed cases of Liddle syndrome are identified in children through evaluation of early-onset hypertension, cases have also been identified later in life (Pepersack et al. 2015). Liddle syndrome has been identified in populations worldwide, although specific genetic lineages might be distributed non-uniformly (Enslow, Stockand, and Berman 2019). The strength of the autosomal dominant mutation has been demonstrated in its persistence in a pedigree through generations. For example, a Liddle syndrome causing mutation may have occurred in a population decades ago, leaving an isolated region with a higher-than-normal prevalence (Pagani et al. 2018).
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Affects of Liddle Syndrome. Estimates of how common Liddle syndrome is vary. A survey of symptoms of veteran patients with hypertension found that 6% met the non-genetic diagnostic criteria for Liddle syndrome (Tapolyai et al. 2010), which is a much higher prevalence than confirmed cases by genetic testing. Gene sequencing studies of early onset hypertension have suggested a population prevalence of about 0.9–1.5% among those who develop hypertension before age 30 (Liu et al. 2018). While most confirmed cases of Liddle syndrome are identified in children through evaluation of early-onset hypertension, cases have also been identified later in life (Pepersack et al. 2015). Liddle syndrome has been identified in populations worldwide, although specific genetic lineages might be distributed non-uniformly (Enslow, Stockand, and Berman 2019). The strength of the autosomal dominant mutation has been demonstrated in its persistence in a pedigree through generations. For example, a Liddle syndrome causing mutation may have occurred in a population decades ago, leaving an isolated region with a higher-than-normal prevalence (Pagani et al. 2018).
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Related disorders of Liddle Syndrome
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Several disorders can produce symptoms similar to Liddle syndrome. These include a mutation to the mineralocorticoid receptor which makes it sensitive to progesterone, mineralocorticoid excess caused by mutations to 11-beta-hydroxysteroiddehydrogenase-type-II enzyme, glucocorticoid remediable aldosteronism and familial glucocorticoid resistance. Excess natural licorice consumption can also cause a transient Liddle-like syndrome. Some similar conditions can also have an autosomal dominant inheritance pattern. For example, primary aldosteronism (Conn’s syndrome) can produce similar symptoms and labs to Liddle syndrome with the exception of a high serum aldosterone level. Gitelman syndrome is a tubulopathy with an autosomal recessive inheritance pattern caused by mutations encoding the sodium-chloride co-transporter, NCC. Like Liddle syndrome it is caused by mutations to a renal sodium transporter. However, Gitelman syndrome causes a loss of sodium in the urine, leading to low blood pressure and other electrolyte abnormalities like hypokalemia, hypomagnesemia and metabolic alkalosis. Bartter syndrome is another tubulopathy, caused by mutations in genes associated with sodium transport in the thick ascending limb. Symptoms include low blood pressure, hypokalemia and metabolic alkalosis. Mutations that cause Bartter syndrome can result from several genes including those for the sodium-potassium-two-chloride symporter (NKCC2), renal outer medullary potassium channel (ROMK) or the calcium-sensing receptor CASR.Salt-sensitivity, often resulting from a mixture of genetic and environmental factors, will also mimic Liddle syndrome. Salt-sensitivity has been associated with chronic kidney disease, older age, obesity and African American ethnicity. Salt-sensitivity will lead to resistant hypertension when not following a low salt diet and lab testing will reveal a low plasma renin activity and low serum aldosterone level. Individuals with salt sensitivity will respond to diuretics, including amiloride.
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Related disorders of Liddle Syndrome. Several disorders can produce symptoms similar to Liddle syndrome. These include a mutation to the mineralocorticoid receptor which makes it sensitive to progesterone, mineralocorticoid excess caused by mutations to 11-beta-hydroxysteroiddehydrogenase-type-II enzyme, glucocorticoid remediable aldosteronism and familial glucocorticoid resistance. Excess natural licorice consumption can also cause a transient Liddle-like syndrome. Some similar conditions can also have an autosomal dominant inheritance pattern. For example, primary aldosteronism (Conn’s syndrome) can produce similar symptoms and labs to Liddle syndrome with the exception of a high serum aldosterone level. Gitelman syndrome is a tubulopathy with an autosomal recessive inheritance pattern caused by mutations encoding the sodium-chloride co-transporter, NCC. Like Liddle syndrome it is caused by mutations to a renal sodium transporter. However, Gitelman syndrome causes a loss of sodium in the urine, leading to low blood pressure and other electrolyte abnormalities like hypokalemia, hypomagnesemia and metabolic alkalosis. Bartter syndrome is another tubulopathy, caused by mutations in genes associated with sodium transport in the thick ascending limb. Symptoms include low blood pressure, hypokalemia and metabolic alkalosis. Mutations that cause Bartter syndrome can result from several genes including those for the sodium-potassium-two-chloride symporter (NKCC2), renal outer medullary potassium channel (ROMK) or the calcium-sensing receptor CASR.Salt-sensitivity, often resulting from a mixture of genetic and environmental factors, will also mimic Liddle syndrome. Salt-sensitivity has been associated with chronic kidney disease, older age, obesity and African American ethnicity. Salt-sensitivity will lead to resistant hypertension when not following a low salt diet and lab testing will reveal a low plasma renin activity and low serum aldosterone level. Individuals with salt sensitivity will respond to diuretics, including amiloride.
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Liddle Syndrome
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Diagnosis of Liddle Syndrome
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Diagnosis of Liddle syndrome often includes identification of symptoms, patient and family history and laboratory testing (e.g., plasma renin activity, serum aldosterone levels). Diagnosis begins with identification of resistant hypertension, and then analysis of laboratory values. This is followed by genetic testing. Clinicians consider the diagnosis of Liddle syndrome when evaluating secondary causes of hypertension and/or difficult-to-control hypertension. Resistant hypertension is defined by the American Heart Association as “blood pressure that remains above goal despite optimal doses of 3 antihypertensive agents of different classes, one ideally being a diuretic.” The gold standard for diagnosing Liddle syndrome is genetic sequencing of the three genes where mutations are known to be associated with Liddle syndrome: SCNN1A, SCNN1B, and SCNN1G. More than 30 different mutations in these genes have been found to cause Liddle syndrome. Most of these mutations are in SCNN1B and SCNN1G genes, and in many patients only these genes will be sequenced. Genetic counseling is recommended prior to testing. A positive genetic test should include communication with the patient about familial decisions and outreach to potentially affected family members.The robust response to amiloride, a potassium sparing diuretic, continues to be integral to the diagnosis of Liddle syndrome. Although other diuretics are often prescribed first for hypertension, other classes of diuretics are not appropriate as they either do not alter the activity of ENaC, or in the case of some other potassium sparing diuretics will not be effective due to the mechanism of Liddle syndrome. A person diagnosed with Liddle syndrome may not develop chronic kidney disease (CKD), but it does preclude them from donating a kidney. Placement on the registry to receive a renal transplant has been effective in some patients, as the replacement of the mutated ENaC with functioning ENaC in the donated kidney may resolve the symptoms of Liddle syndrome.
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Diagnosis of Liddle Syndrome. Diagnosis of Liddle syndrome often includes identification of symptoms, patient and family history and laboratory testing (e.g., plasma renin activity, serum aldosterone levels). Diagnosis begins with identification of resistant hypertension, and then analysis of laboratory values. This is followed by genetic testing. Clinicians consider the diagnosis of Liddle syndrome when evaluating secondary causes of hypertension and/or difficult-to-control hypertension. Resistant hypertension is defined by the American Heart Association as “blood pressure that remains above goal despite optimal doses of 3 antihypertensive agents of different classes, one ideally being a diuretic.” The gold standard for diagnosing Liddle syndrome is genetic sequencing of the three genes where mutations are known to be associated with Liddle syndrome: SCNN1A, SCNN1B, and SCNN1G. More than 30 different mutations in these genes have been found to cause Liddle syndrome. Most of these mutations are in SCNN1B and SCNN1G genes, and in many patients only these genes will be sequenced. Genetic counseling is recommended prior to testing. A positive genetic test should include communication with the patient about familial decisions and outreach to potentially affected family members.The robust response to amiloride, a potassium sparing diuretic, continues to be integral to the diagnosis of Liddle syndrome. Although other diuretics are often prescribed first for hypertension, other classes of diuretics are not appropriate as they either do not alter the activity of ENaC, or in the case of some other potassium sparing diuretics will not be effective due to the mechanism of Liddle syndrome. A person diagnosed with Liddle syndrome may not develop chronic kidney disease (CKD), but it does preclude them from donating a kidney. Placement on the registry to receive a renal transplant has been effective in some patients, as the replacement of the mutated ENaC with functioning ENaC in the donated kidney may resolve the symptoms of Liddle syndrome.
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Liddle Syndrome
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Therapies of Liddle Syndrome
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The goal of treatment is to resolve the patient’s hypertension, lowering blood pressure measurements to achieve guideline targets of control. A controlled blood pressure reduces cardiovascular risk and often has a positive effect on the patient’s overall health, including mental health.In a patient with Liddle syndrome the response to standard treatments for hypertension such as thiazide diuretics or ACE inhibitors may be reduced compared to other hypertensive patients, especially in the absence of treatment with amiloride. This may lead healthcare providers to falsely believe that patients are failing to comply with prescribed medication regimens. Repeated questioning of patient compliance to medication regimens can have psychological and emotional consequences. For this reason, response to amiloride should be considered in the process of diagnosing Liddle syndrome and developing a treatment plan.Amiloride
Amiloride is the first-line treatment of Liddle syndrome. It targets and blocks ENaC in the kidney, thereby directly countering the pathologic pathway. Other potassium sparing diuretics, like triamterene, eplerenone, spironolactone and finerenone are less effective or ineffective. Eplerenone, spironolactone and finerenone have mechanisms of action different from amiloride and triamterene which renders them ineffective in the treatment of Liddle syndrome. For example, spironolactone antagonizes binding of aldosterone to its receptor, preventing aldosterone from binding and acting in cells in the kidney. In patients with Liddle syndrome, aldosterone levels are low, and so inhibiting aldosterone’s action with spironolactone has little effect. In fact, the lack of response to spironolactone was a feature identified by Grant Liddle in his initial description of Liddle syndrome. Despite triamterene being described as the first effective treatment for Liddle syndrome, amiloride has superior efficacy to triamterene and is preferred. When the diagnosis of Liddle syndrome is made later in life, additional anti-hypertensive medications are also needed to achieve blood pressure control. Amiloride is not time-release formulated, and it is recommended to take at similar times each day, some patients with Liddle syndrome may opt for a twice daily regimen. The treatment is life-long. Amiloride is available for custom-compounding by pharmacists. The pharmacist can prepare a dose in capsule form, without other medications or stabilizing compounds. This specialized formulation may be appropriate for ‘fine-tuning’ dose level. While amiloride does not have sufficient data in pregnant women to be confirmed as safe, it has not been found to cause fetal harm in animal studies. Women with Liddle syndrome have continued amiloride in pregnancy without fetal or maternal complications. Blood pressure during pregnancy may be difficult to treat without amiloride, particularly in the 3rd trimester.Diet
Limiting salt in the diet is an important component to the medical management of hypertension. In Liddle syndrome, a low salt-diet is particularly effective, especially when paired with amiloride. Because sodium retention is directly involved in the mechanism of persistent hypertension in Liddle syndrome, a low sodium diet can be helpful in achieving a goal blood pressure (Pagani et al. 2018). Genetic counseling is recommended for patients with Liddle syndrome and their family members.
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Therapies of Liddle Syndrome. The goal of treatment is to resolve the patient’s hypertension, lowering blood pressure measurements to achieve guideline targets of control. A controlled blood pressure reduces cardiovascular risk and often has a positive effect on the patient’s overall health, including mental health.In a patient with Liddle syndrome the response to standard treatments for hypertension such as thiazide diuretics or ACE inhibitors may be reduced compared to other hypertensive patients, especially in the absence of treatment with amiloride. This may lead healthcare providers to falsely believe that patients are failing to comply with prescribed medication regimens. Repeated questioning of patient compliance to medication regimens can have psychological and emotional consequences. For this reason, response to amiloride should be considered in the process of diagnosing Liddle syndrome and developing a treatment plan.Amiloride
Amiloride is the first-line treatment of Liddle syndrome. It targets and blocks ENaC in the kidney, thereby directly countering the pathologic pathway. Other potassium sparing diuretics, like triamterene, eplerenone, spironolactone and finerenone are less effective or ineffective. Eplerenone, spironolactone and finerenone have mechanisms of action different from amiloride and triamterene which renders them ineffective in the treatment of Liddle syndrome. For example, spironolactone antagonizes binding of aldosterone to its receptor, preventing aldosterone from binding and acting in cells in the kidney. In patients with Liddle syndrome, aldosterone levels are low, and so inhibiting aldosterone’s action with spironolactone has little effect. In fact, the lack of response to spironolactone was a feature identified by Grant Liddle in his initial description of Liddle syndrome. Despite triamterene being described as the first effective treatment for Liddle syndrome, amiloride has superior efficacy to triamterene and is preferred. When the diagnosis of Liddle syndrome is made later in life, additional anti-hypertensive medications are also needed to achieve blood pressure control. Amiloride is not time-release formulated, and it is recommended to take at similar times each day, some patients with Liddle syndrome may opt for a twice daily regimen. The treatment is life-long. Amiloride is available for custom-compounding by pharmacists. The pharmacist can prepare a dose in capsule form, without other medications or stabilizing compounds. This specialized formulation may be appropriate for ‘fine-tuning’ dose level. While amiloride does not have sufficient data in pregnant women to be confirmed as safe, it has not been found to cause fetal harm in animal studies. Women with Liddle syndrome have continued amiloride in pregnancy without fetal or maternal complications. Blood pressure during pregnancy may be difficult to treat without amiloride, particularly in the 3rd trimester.Diet
Limiting salt in the diet is an important component to the medical management of hypertension. In Liddle syndrome, a low salt-diet is particularly effective, especially when paired with amiloride. Because sodium retention is directly involved in the mechanism of persistent hypertension in Liddle syndrome, a low sodium diet can be helpful in achieving a goal blood pressure (Pagani et al. 2018). Genetic counseling is recommended for patients with Liddle syndrome and their family members.
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Overview of Limb-Girdle Muscular Dystrophies
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Limb-girdle muscular dystrophies (LGMD) are a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Many different subtypes have been identified based upon abnormal changes (mutations) of certain genes. The age at onset, severity, and progression of symptoms of these subtypes may vary greatly from case to case, even among individuals in the same family. Some individuals may have a mild, slowly progressive form of the disorders; other may have a rapidly progressive form of the disorder that causes severe disability.The term limb-girdle muscular dystrophies is a general term that encompasses several disorders. These disorders can now be distinguished by genetic and protein analysis. The various forms of LGMD may be inherited as autosomal dominant or recessive traits. Autosomal dominant LGMD is known as LGMD1 and there are currently recognized eight subtypes (LGMD1A-1H). Autosomal recessive LGMD is known as LGMD2 and has 17 subtypes (LGMDA-Q).Additional terminology has been used in the past to describe forms of muscular dystrophy that are now classified under LGMD. These terms are no longer widely used and include scapulohumeral (Erb) muscular dystrophy, pelvifemoral (Leyden-Mobius) muscular dystrophy, and severe childhood autosomal recessive muscular dystrophy (SCARMD).
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Overview of Limb-Girdle Muscular Dystrophies. Limb-girdle muscular dystrophies (LGMD) are a group of rare progressive genetic disorders that are characterized by wasting (atrophy) and weakness of the voluntary muscles of the hip and shoulder areas (limb-girdle area). Muscle weakness and atrophy are progressive and may spread to affect other muscles of the body. Many different subtypes have been identified based upon abnormal changes (mutations) of certain genes. The age at onset, severity, and progression of symptoms of these subtypes may vary greatly from case to case, even among individuals in the same family. Some individuals may have a mild, slowly progressive form of the disorders; other may have a rapidly progressive form of the disorder that causes severe disability.The term limb-girdle muscular dystrophies is a general term that encompasses several disorders. These disorders can now be distinguished by genetic and protein analysis. The various forms of LGMD may be inherited as autosomal dominant or recessive traits. Autosomal dominant LGMD is known as LGMD1 and there are currently recognized eight subtypes (LGMD1A-1H). Autosomal recessive LGMD is known as LGMD2 and has 17 subtypes (LGMDA-Q).Additional terminology has been used in the past to describe forms of muscular dystrophy that are now classified under LGMD. These terms are no longer widely used and include scapulohumeral (Erb) muscular dystrophy, pelvifemoral (Leyden-Mobius) muscular dystrophy, and severe childhood autosomal recessive muscular dystrophy (SCARMD).
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Symptoms of Limb-Girdle Muscular Dystrophies
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Although there are some common themes recognizable in the main types of LGMD, the age at onset, severity, and progression of symptoms associated with LGMD may vary greatly from case to case, even among members of the same family. Some cases of LGMD may have onset during adulthood, mild symptoms, and slow progression; others may have onset during childhood and early severe disability such as difficulty climbing stairs and walking. Some individuals eventually require a wheelchair. In most cases, childhood onset of LGMD results in a more severe disorder that progresses more rapidly than adolescent or adult onset cases.The major symptoms of LGMD are progressive wasting (atrophy) and weakness of the proximal muscles of the hip and shoulder areas. Proximal muscles are the muscles that are closest to the center of the body such as the muscles of the shoulder, pelvis, and upper arms and legs. Muscle weakness may spread from the proximal muscles to affect distal muscles. Distal muscles are those farther from the center of the body and include the muscles of the lower arms and legs and the hands and feet.Muscle weakness usually affects the muscles of the pelvic and hip area first and affected individuals may have difficulty standing from a sitting position or walking up stairs. Weakness of the hip and upper leg muscles may cause a distinctive waddling gait. Eventually, muscle weakness affects the muscles of the upper arms and shoulders (limb-girdle area). Consequently, affected individuals may have difficultly raising their arms over their heads or carrying heavy objects. Muscle weakness may be associated with soreness in the muscles and joint pain.Additional abnormalities that may develop in individuals with LGMD include abnormal side-to-side curvature of the spine (scoliosis), abnormal front-to-back curvature of the spine (lordosis), thickening and shortening of tissue that cause deformity and restricts movement of affected areas, especially the joints (contractures), and overgrowth (hypertrophy) of certain muscles such as the calf muscle.In some particular forms of LGMD, weakening of the heart muscle, known as cardiomyopathy, can occur. Cardiomyopathy is a progressive condition that may result in an impaired ability of the heart to pump blood; fatigue; heart block; irregular heartbeats (arrhythmias) and, potentially, heart failure. Heart abnormalities are not associated with all forms of LGMD.The muscles of the respiratory system may also become involved in some cases resulting in difficulty swallowing (dysphagia), slurred speech (dysarthria), and breathing difficulties. Breathing difficulties may become progressively worse in such cases.AUTOSOMAL RECESSIVE LGMDAt least 17 different forms of autosomal recessive LGMD have been identified. These disorders are characterized by progressive weakness of the muscles of the pelvic girdle, legs, arms and shoulders. Progression of muscle weakness may be slow or rapid and may vary even among individuals in the same family. Intelligence is normal. The age of onset varies from subgroup to subgroup. Overall, onset is more common in childhood but it may even occur late in adult life.LGMD2A (calpain-deficient LGMD; calpainopathy)This form of LGMD usually affects children between the ages of 8-15, but may range from 2-40 years of age. Most cases are characterized by muscle weakness affecting the hip-girdle area although the hip adductor muscles may be spared. Degeneration (atrophy) is prominent. Affected children may exhibit a distinct waddling gait and may fall frequently. They may also experience difficulty running and climbing stairs. Respiratory problems have been reported with this form of LGMD, but heart abnormalities have not been.LGMD2B (dysferlinopathy)Onset of this form of LGMD is usually during the juvenile years. Most individuals have normal mobility during childhood. Muscle weakness affects muscles of both the pelvic and shoulder area, but usually progresses very slowly. Wasting (atrophy) of the calf muscle and an inability to walk on tiptoes may be seen early in the disease progression. In rare cases, temporary (transient) overgrowth of the calf muscle, painful swelling of the calf, and early development of contractures may occur. The heart and respiratory muscles are usually not affected.LGMD2B is caused by mutations of a gene that also causes Miyoshi myopathy a rare muscle disorder characterized by weakness of the distal muscles of the legs and arms. Families have been reported in which some members develop LGMD2B and others Miyoshi myopathy. (For more information on this disorder, choose “Miyoshi” as your search term in the Rare Disease Database.)LGMD2C-2F (sarcoglycanopathies)These forms of LGMD may range from a severe form often with childhood onset to a mild form often with adult onset. The severity varies greatly even among individuals of the same family. Early onset forms may cause progressive muscle weakness of the legs, hips, abdomen, and shoulder. The progression of muscle weakness of the sarcoglycanopathies is often more rapid than with other forms of LGMD and affected individuals may need a wheelchair between 12-16 years of age. Individuals with later onset usually experience a slower progression and more mild symptoms. Such individuals usually retain the ability to walk independently late into adulthood.Additional symptoms are often associated with the sarcoglycanopathies including overgrowth of the calf and tongue muscles, cardiomyopathy, respiratory abnormalities, contractures, and scoliosis.LGMD2G (telethoninopathy)This form of LGMD usually becomes apparent during childhood or adolescence and presents with muscle weakness of the upper and lower legs. Affected children may have difficulty climbing stairs and running. Affected individuals often need a wheelchair by the third or fourth decade. Heart abnormalities have occurred in approximately half of the reported cases. Overgrowth (hypertrophy) of the calf muscle may also occur.LGMD2H (TRIM 32 mutations)This form of LGMD has been reported in the Hutterite population of Manitoba, Canada. Affected individuals develop weakness of the lower limbs that may be mild or severe. Weakness of facial muscles may also occur. As the disease progresses, muscles of the arms may become involved. Affected individuals may remain able to walk well into adulthood.LGMD2I (fukutin-related proteinopathy)This form of LGMD may range from mild to severe. Early childhood onset of LGMD2I usually indicates a severe clinical course with affected individuals needing a wheelchair by the second decade. There is overlap with a congenital form of muscular dystrophy, MDC1C. In such cases, affected individuals have severe muscle weakness of both the arms and legs, loss of muscle tone (hypotonia), and delays in attaining motor milestones. The late or adult onset form of LGMD2I is a slowly progressive, mild form of the disorder. LGMD2I is also associated with cardiomyopathy and respiratory abnormalities.LGMD2J (titinopathy)This form of LGMD occurs when two titin gene mutations are present and has a variable age of onset ranging from 10-30 years. Affected individuals have severe progressive proximal muscle weakness. Eventually the distal muscles become involved and some individuals may require the use of a wheelchair. When only one titin gene mutation is present, distal myopathy can result. LGMD2J has been reported in Finnish individuals.LGMD2KThis extremely rare form of LGMD has been reported in Turkish individuals. Onset is during infancy or early childhood. Affected individuals display slowly progressive muscle weakness and most retain the ability to walk into late adolescence. All affected individuals had developmentaldelays.LGMD2L (anoctominopathy)Affected individuals were reported to have proximal muscle weakness in lower and upper limbs and muscle hypertrophy was common. Intelligence was reported to be normal.Causative genes have been identified for LGMD2K, LGMD2L, LGMD2M, LGMD2N, LGMD2O, LGMD2Q and recessive LGMD with primary alpha-dystroglycan defect.AUTOSOMAL DOMINANT LGMDThe autosomal dominant forms of LGMD occur less frequently than the autosomal recessive forms and are more likely to occur later during life. In many cases, autosomal dominant LGMD progresses at a slower rate than autosomal recessive LGMD and has symptoms can be variable, even among members of the same family. Each gene mutation can lead to many different groups of symptoms. Examples of some of the symptoms that can be associated with specific gene mutations are as follows:LGMD1A (myotilinopathy)The onset of LGMD1A varies, ranging from adolescence to adulthood. This form of LGMD is characterized by proximal muscle weakness sometimes associated with slurred speech (dysarthria) and an abnormally tight Achilles tendon. Muscle weakness in the arms may also occur. The distal muscles may eventually become involved as well. The progression of LGMD1A is extremely slow and only a few affected individuals eventually need a wheelchair. Heart involvement has been noted in some cases. This phenotype overlaps with the group of diseases known as myofibrillar myopathies, another heterogeneous group of muscle diseases, which may also be associated with myotilin mutations.LGMD1B (lamin A/C)This form of LGMD is characterized by slowly progressive proximal muscle weakness. Affected individuals may also develop overgrowth (hypertrophy) of calf muscles and mild contractures of the elbows or Achilles tendon. Heart abnormalities are frequent and should be screened for including progressive conduction defects that can ultimately lead to irregular heartbeats (arrhythmias) and heart block. Lamin A/C mutations can result in a wide range of different phenotypes so care is required to offer genetic testing in families known to be affected.LGMD1C (caveolinopathy)This form of LGMD is characterized by cramping muscle pain after exercise, mild to moderate proximal muscle weakness, and overgrowth of the calf muscle. Progression of muscle weakness may be slow or rapid. Onset is usually during early childhood. Patients may have so called rippling muscles.LGMD1DThis extremely rare form of LGMD is characterized by progressive muscle weakness that first affects the hip-girdle area before spreading to affect the limb-girdle area. Onset is usually during early adulthood, but may occur as late as the sixth decade. The progression of the disorder is slow. Heart defects including conduction abnormalities and dilated cardiomyopathy may occur. Individuals with this form of LGMD usually remain able to walk.LGMD1EThis form of LGMD is associated with progressive weakness of the proximal muscles of the upper and lower legs. Onset is usually during childhood and the progression of the disease is slow. Affected individuals may also develop difficulty swallowing (dysphagia) and contractures. Heart abnormalities occur in this form of LGMD usually one or two decades after development of muscle weakness.Causative genes have not been identified for LGMD1E, LGMD1F, LGMD1G, or LGMD 1H.Additional cases of LGMD have been reported in the medical literature that have not been linked to any of the abovementioned subtypes and for which no causative gene has been identified. This means that further LGMD genes probably still remain to be identified.
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Symptoms of Limb-Girdle Muscular Dystrophies. Although there are some common themes recognizable in the main types of LGMD, the age at onset, severity, and progression of symptoms associated with LGMD may vary greatly from case to case, even among members of the same family. Some cases of LGMD may have onset during adulthood, mild symptoms, and slow progression; others may have onset during childhood and early severe disability such as difficulty climbing stairs and walking. Some individuals eventually require a wheelchair. In most cases, childhood onset of LGMD results in a more severe disorder that progresses more rapidly than adolescent or adult onset cases.The major symptoms of LGMD are progressive wasting (atrophy) and weakness of the proximal muscles of the hip and shoulder areas. Proximal muscles are the muscles that are closest to the center of the body such as the muscles of the shoulder, pelvis, and upper arms and legs. Muscle weakness may spread from the proximal muscles to affect distal muscles. Distal muscles are those farther from the center of the body and include the muscles of the lower arms and legs and the hands and feet.Muscle weakness usually affects the muscles of the pelvic and hip area first and affected individuals may have difficulty standing from a sitting position or walking up stairs. Weakness of the hip and upper leg muscles may cause a distinctive waddling gait. Eventually, muscle weakness affects the muscles of the upper arms and shoulders (limb-girdle area). Consequently, affected individuals may have difficultly raising their arms over their heads or carrying heavy objects. Muscle weakness may be associated with soreness in the muscles and joint pain.Additional abnormalities that may develop in individuals with LGMD include abnormal side-to-side curvature of the spine (scoliosis), abnormal front-to-back curvature of the spine (lordosis), thickening and shortening of tissue that cause deformity and restricts movement of affected areas, especially the joints (contractures), and overgrowth (hypertrophy) of certain muscles such as the calf muscle.In some particular forms of LGMD, weakening of the heart muscle, known as cardiomyopathy, can occur. Cardiomyopathy is a progressive condition that may result in an impaired ability of the heart to pump blood; fatigue; heart block; irregular heartbeats (arrhythmias) and, potentially, heart failure. Heart abnormalities are not associated with all forms of LGMD.The muscles of the respiratory system may also become involved in some cases resulting in difficulty swallowing (dysphagia), slurred speech (dysarthria), and breathing difficulties. Breathing difficulties may become progressively worse in such cases.AUTOSOMAL RECESSIVE LGMDAt least 17 different forms of autosomal recessive LGMD have been identified. These disorders are characterized by progressive weakness of the muscles of the pelvic girdle, legs, arms and shoulders. Progression of muscle weakness may be slow or rapid and may vary even among individuals in the same family. Intelligence is normal. The age of onset varies from subgroup to subgroup. Overall, onset is more common in childhood but it may even occur late in adult life.LGMD2A (calpain-deficient LGMD; calpainopathy)This form of LGMD usually affects children between the ages of 8-15, but may range from 2-40 years of age. Most cases are characterized by muscle weakness affecting the hip-girdle area although the hip adductor muscles may be spared. Degeneration (atrophy) is prominent. Affected children may exhibit a distinct waddling gait and may fall frequently. They may also experience difficulty running and climbing stairs. Respiratory problems have been reported with this form of LGMD, but heart abnormalities have not been.LGMD2B (dysferlinopathy)Onset of this form of LGMD is usually during the juvenile years. Most individuals have normal mobility during childhood. Muscle weakness affects muscles of both the pelvic and shoulder area, but usually progresses very slowly. Wasting (atrophy) of the calf muscle and an inability to walk on tiptoes may be seen early in the disease progression. In rare cases, temporary (transient) overgrowth of the calf muscle, painful swelling of the calf, and early development of contractures may occur. The heart and respiratory muscles are usually not affected.LGMD2B is caused by mutations of a gene that also causes Miyoshi myopathy a rare muscle disorder characterized by weakness of the distal muscles of the legs and arms. Families have been reported in which some members develop LGMD2B and others Miyoshi myopathy. (For more information on this disorder, choose “Miyoshi” as your search term in the Rare Disease Database.)LGMD2C-2F (sarcoglycanopathies)These forms of LGMD may range from a severe form often with childhood onset to a mild form often with adult onset. The severity varies greatly even among individuals of the same family. Early onset forms may cause progressive muscle weakness of the legs, hips, abdomen, and shoulder. The progression of muscle weakness of the sarcoglycanopathies is often more rapid than with other forms of LGMD and affected individuals may need a wheelchair between 12-16 years of age. Individuals with later onset usually experience a slower progression and more mild symptoms. Such individuals usually retain the ability to walk independently late into adulthood.Additional symptoms are often associated with the sarcoglycanopathies including overgrowth of the calf and tongue muscles, cardiomyopathy, respiratory abnormalities, contractures, and scoliosis.LGMD2G (telethoninopathy)This form of LGMD usually becomes apparent during childhood or adolescence and presents with muscle weakness of the upper and lower legs. Affected children may have difficulty climbing stairs and running. Affected individuals often need a wheelchair by the third or fourth decade. Heart abnormalities have occurred in approximately half of the reported cases. Overgrowth (hypertrophy) of the calf muscle may also occur.LGMD2H (TRIM 32 mutations)This form of LGMD has been reported in the Hutterite population of Manitoba, Canada. Affected individuals develop weakness of the lower limbs that may be mild or severe. Weakness of facial muscles may also occur. As the disease progresses, muscles of the arms may become involved. Affected individuals may remain able to walk well into adulthood.LGMD2I (fukutin-related proteinopathy)This form of LGMD may range from mild to severe. Early childhood onset of LGMD2I usually indicates a severe clinical course with affected individuals needing a wheelchair by the second decade. There is overlap with a congenital form of muscular dystrophy, MDC1C. In such cases, affected individuals have severe muscle weakness of both the arms and legs, loss of muscle tone (hypotonia), and delays in attaining motor milestones. The late or adult onset form of LGMD2I is a slowly progressive, mild form of the disorder. LGMD2I is also associated with cardiomyopathy and respiratory abnormalities.LGMD2J (titinopathy)This form of LGMD occurs when two titin gene mutations are present and has a variable age of onset ranging from 10-30 years. Affected individuals have severe progressive proximal muscle weakness. Eventually the distal muscles become involved and some individuals may require the use of a wheelchair. When only one titin gene mutation is present, distal myopathy can result. LGMD2J has been reported in Finnish individuals.LGMD2KThis extremely rare form of LGMD has been reported in Turkish individuals. Onset is during infancy or early childhood. Affected individuals display slowly progressive muscle weakness and most retain the ability to walk into late adolescence. All affected individuals had developmentaldelays.LGMD2L (anoctominopathy)Affected individuals were reported to have proximal muscle weakness in lower and upper limbs and muscle hypertrophy was common. Intelligence was reported to be normal.Causative genes have been identified for LGMD2K, LGMD2L, LGMD2M, LGMD2N, LGMD2O, LGMD2Q and recessive LGMD with primary alpha-dystroglycan defect.AUTOSOMAL DOMINANT LGMDThe autosomal dominant forms of LGMD occur less frequently than the autosomal recessive forms and are more likely to occur later during life. In many cases, autosomal dominant LGMD progresses at a slower rate than autosomal recessive LGMD and has symptoms can be variable, even among members of the same family. Each gene mutation can lead to many different groups of symptoms. Examples of some of the symptoms that can be associated with specific gene mutations are as follows:LGMD1A (myotilinopathy)The onset of LGMD1A varies, ranging from adolescence to adulthood. This form of LGMD is characterized by proximal muscle weakness sometimes associated with slurred speech (dysarthria) and an abnormally tight Achilles tendon. Muscle weakness in the arms may also occur. The distal muscles may eventually become involved as well. The progression of LGMD1A is extremely slow and only a few affected individuals eventually need a wheelchair. Heart involvement has been noted in some cases. This phenotype overlaps with the group of diseases known as myofibrillar myopathies, another heterogeneous group of muscle diseases, which may also be associated with myotilin mutations.LGMD1B (lamin A/C)This form of LGMD is characterized by slowly progressive proximal muscle weakness. Affected individuals may also develop overgrowth (hypertrophy) of calf muscles and mild contractures of the elbows or Achilles tendon. Heart abnormalities are frequent and should be screened for including progressive conduction defects that can ultimately lead to irregular heartbeats (arrhythmias) and heart block. Lamin A/C mutations can result in a wide range of different phenotypes so care is required to offer genetic testing in families known to be affected.LGMD1C (caveolinopathy)This form of LGMD is characterized by cramping muscle pain after exercise, mild to moderate proximal muscle weakness, and overgrowth of the calf muscle. Progression of muscle weakness may be slow or rapid. Onset is usually during early childhood. Patients may have so called rippling muscles.LGMD1DThis extremely rare form of LGMD is characterized by progressive muscle weakness that first affects the hip-girdle area before spreading to affect the limb-girdle area. Onset is usually during early adulthood, but may occur as late as the sixth decade. The progression of the disorder is slow. Heart defects including conduction abnormalities and dilated cardiomyopathy may occur. Individuals with this form of LGMD usually remain able to walk.LGMD1EThis form of LGMD is associated with progressive weakness of the proximal muscles of the upper and lower legs. Onset is usually during childhood and the progression of the disease is slow. Affected individuals may also develop difficulty swallowing (dysphagia) and contractures. Heart abnormalities occur in this form of LGMD usually one or two decades after development of muscle weakness.Causative genes have not been identified for LGMD1E, LGMD1F, LGMD1G, or LGMD 1H.Additional cases of LGMD have been reported in the medical literature that have not been linked to any of the abovementioned subtypes and for which no causative gene has been identified. This means that further LGMD genes probably still remain to be identified.
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Limb-Girdle Muscular Dystrophies
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Causes of Limb-Girdle Muscular Dystrophies
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LGMD is a genetic disorder that is inherited as either an autosomal recessive or dominant trait. The autosomal recessive forms are estimated to account for 90 percent of cases. Genetic disorders are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. In some cases, dominant genetic mutations may occur spontaneously for no apparent reason in families without a previous history of the mutation (sporadic mutation). This “new” mutation is then passed on as an autosomal dominant trait.Researchers have identified many different subtypes of LGMD, each one resulting from a mutation of a different disease gene (genetic heterogeneity). The genes associated with many of these subtypes have been identified. Most of these genes are involved in the production of certain muscle proteins. These proteins may be located on the membrane surrounding each muscle cell or within the cell itself. The membrane surrounding each muscle cell, known as the sacrolemma, protects the cells from injury and serves as a gate that allows or prevents substances into the cell. If one of the proteins is missing or defective, muscle cells may be damaged or may incorrectly allow substances in or out of the cell, eventually resulting in the symptoms of LGMD. The exact role and function of all these proteins and how their deficiency or absence causes LGMD is not yet known.The genes associated with the various types of LGMD are listed in the Gene table of monogenic neuromuscular disorders found in the following link:http://www.snmo.sk/publikacie/subory/Neurogenetics%20NMO%202011.pdf
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Causes of Limb-Girdle Muscular Dystrophies. LGMD is a genetic disorder that is inherited as either an autosomal recessive or dominant trait. The autosomal recessive forms are estimated to account for 90 percent of cases. Genetic disorders are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. In some cases, dominant genetic mutations may occur spontaneously for no apparent reason in families without a previous history of the mutation (sporadic mutation). This “new” mutation is then passed on as an autosomal dominant trait.Researchers have identified many different subtypes of LGMD, each one resulting from a mutation of a different disease gene (genetic heterogeneity). The genes associated with many of these subtypes have been identified. Most of these genes are involved in the production of certain muscle proteins. These proteins may be located on the membrane surrounding each muscle cell or within the cell itself. The membrane surrounding each muscle cell, known as the sacrolemma, protects the cells from injury and serves as a gate that allows or prevents substances into the cell. If one of the proteins is missing or defective, muscle cells may be damaged or may incorrectly allow substances in or out of the cell, eventually resulting in the symptoms of LGMD. The exact role and function of all these proteins and how their deficiency or absence causes LGMD is not yet known.The genes associated with the various types of LGMD are listed in the Gene table of monogenic neuromuscular disorders found in the following link:http://www.snmo.sk/publikacie/subory/Neurogenetics%20NMO%202011.pdf
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Limb-Girdle Muscular Dystrophies
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Affects of Limb-Girdle Muscular Dystrophies
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LGMD affects males and females in equal numbers. The incidence of the disorder is unknown. The prevalence of LGMD is unknown, but estimates range from one in 14,500 to one in 123,000. The age of onset can vary greatly even among individuals of the same family. The relative frequencies of the different types of LGMD vary from population to population, but worldwide LGMD2G, 2H and 2J are extremely rare.
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Affects of Limb-Girdle Muscular Dystrophies. LGMD affects males and females in equal numbers. The incidence of the disorder is unknown. The prevalence of LGMD is unknown, but estimates range from one in 14,500 to one in 123,000. The age of onset can vary greatly even among individuals of the same family. The relative frequencies of the different types of LGMD vary from population to population, but worldwide LGMD2G, 2H and 2J are extremely rare.
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Limb-Girdle Muscular Dystrophies
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Related disorders of Limb-Girdle Muscular Dystrophies
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Symptoms of the following disorders can be similar to those of LGMD. Comparisons may be useful for a differential diagnosis.The dystrophinopathies are a spectrum of muscle diseases caused by mutations of the mutations of the DMD gene located on the X chromosome. The severe end of the spectrum includes muscles diseases known as Duchenne muscular dystrophy and Becker muscular dystrophy. Duchenne muscular dystrophy is the most prevalent form of childhood muscular dystrophy. The disorder typically is recognized from approximately age three to six years and has a relatively rapid, progressive disease course. Duchenne muscular dystrophy is initially characterized by muscle weakness and wasting (atrophy) within the pelvic area that may be followed by involvement of the shoulder muscles. As the disease progresses, muscle weakness and atrophy spread to affect the trunk and forearms and gradually progress to involve most major muscles of the body. Becker muscular dystrophy usually begins during the second or third decade of life. This slowly progressive disorder affects males almost exclusively. Muscles of the hips and shoulders are weakened, walking abnormalities develop, and mild mental retardation may be present. Eventually, other more severe symptoms may involve the heart and lungs. Both Duchenne and Becker muscular dystrophy are inherited as X-linked recessive traits. (For more information about these disorders, choose “Duchenne or Becker” as your search in the Rare Disease Database.)Dystrophinopathy is more common than any form of LGMD and should also be considered in any patient presenting with limb girdle weakness. The diagnosis should be considered also in women as carriers of dystrophinopathy can in some cases have muscle symptoms.Facioscapulohumeral muscular dystrophy (FSHD), also known as Landouzy-Dejerine muscular dystrophy, is another neuromuscular disorder which may overlap in symptoms with forms of LGMD. Symptom onset usually occurs in adolescence or early adulthood; however, less commonly, symptoms may become apparent as early as infancy or early childhood. The disorder is typically initially characterized by weakness of facial, shoulder, and/or upper arm muscles. Associated abnormalities may include an impaired ability to completely close the eyes, limited movements of the lips, and difficulties raising the arms over the head. Affected individuals may also eventually develop weakness and associated wasting (atrophy) of muscles of the hips and thighs and/or involvement of lower leg muscles. Although the disease course may be variable, FSHD is most typically characterized by relatively slow disease progression. Specific symptoms and findings may also vary in range and severity, including among affected members of the same family (kindred). FSHD is usually inherited as an autosomal dominant trait. However, in up to approximately 30 percent of affected individuals, there is no apparent family history of the disorder. In some of these cases, FSHD may be due to new genetic changes (mutations) that appear to occur spontaneously for unknown reasons (sporadically). (For more information on this disorder, choose “facioscapulohumeral muscular dystrophy” as your search term in the Rare Disease Database.)Emery-Dreifuss muscular dystrophy (EDMD) is a rare, often slowly progressive form of muscular dystrophy affecting the muscles of the arms, legs, face, neck, spine and heart. The disorder consists of weakness and degeneration of certain muscles, joints that are fixed in a flexed or extended position (contractures), and abnormalities affecting the heart (cardiomyopathy). Major symptoms may include muscle wasting and weakness particularly in the upper legs and arms and contractures of the elbows, Achilles tendons, and upper back muscles. In some cases, additional abnormalities may be present. In most cases, muscle weakness is slowly progressive. Heart abnormalities can potentially result in life-threatening complications. EDMD is usually inherited as an x-linked recessive trait, but may also be inherited as an autosomal dominant or autosomal recessive trait. Autosomal dominant Emery Dreifuss muscular dystrophy is caused by mutations in lamin A/C, the same gene involved in LGMD1B and there may be significant clinical overlaps. (For more information about this condition, choose “Emery Dreifuss” as your search term in the Rare Disease Database.)Spinal muscular atrophy (SMA) that is caused by a deletion of the SMN gene on chromosome 5 is an inherited progressive neuromuscular disorder characterized by degeneration of groups of nerve cells (motor nuclei) within the lowest region of the brain (lower brainstem) and certain motor neurons in the spinal cord (anterior horn cells). Motor neurons are nerve cells that transmit nerve impulses from the spinal cord or brain (central nervous system) to muscle or glandular tissue. Typical symptoms are a slowly progressive muscle weakness and muscle wasting (atrophy). Affected individuals have poor muscle tone, muscle weakness on both sides of the body without, or with minimal, involvement of the face muscles, twitching tongue and a lack of deep tendon reflexes. SMA is divided into subtypes based on age of onset of symptoms and maximum function achieved. (For more information on this disorder, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.)Additional forms of muscle disease (myopathy) are considered differential diagnoses for LGMD including metabolic myopathies such as Pompe disease; inflammatory myopathies such as dermatomyositis or polymyositis; and distinct congenital myopathies such as nemaline myopathy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Related disorders of Limb-Girdle Muscular Dystrophies. Symptoms of the following disorders can be similar to those of LGMD. Comparisons may be useful for a differential diagnosis.The dystrophinopathies are a spectrum of muscle diseases caused by mutations of the mutations of the DMD gene located on the X chromosome. The severe end of the spectrum includes muscles diseases known as Duchenne muscular dystrophy and Becker muscular dystrophy. Duchenne muscular dystrophy is the most prevalent form of childhood muscular dystrophy. The disorder typically is recognized from approximately age three to six years and has a relatively rapid, progressive disease course. Duchenne muscular dystrophy is initially characterized by muscle weakness and wasting (atrophy) within the pelvic area that may be followed by involvement of the shoulder muscles. As the disease progresses, muscle weakness and atrophy spread to affect the trunk and forearms and gradually progress to involve most major muscles of the body. Becker muscular dystrophy usually begins during the second or third decade of life. This slowly progressive disorder affects males almost exclusively. Muscles of the hips and shoulders are weakened, walking abnormalities develop, and mild mental retardation may be present. Eventually, other more severe symptoms may involve the heart and lungs. Both Duchenne and Becker muscular dystrophy are inherited as X-linked recessive traits. (For more information about these disorders, choose “Duchenne or Becker” as your search in the Rare Disease Database.)Dystrophinopathy is more common than any form of LGMD and should also be considered in any patient presenting with limb girdle weakness. The diagnosis should be considered also in women as carriers of dystrophinopathy can in some cases have muscle symptoms.Facioscapulohumeral muscular dystrophy (FSHD), also known as Landouzy-Dejerine muscular dystrophy, is another neuromuscular disorder which may overlap in symptoms with forms of LGMD. Symptom onset usually occurs in adolescence or early adulthood; however, less commonly, symptoms may become apparent as early as infancy or early childhood. The disorder is typically initially characterized by weakness of facial, shoulder, and/or upper arm muscles. Associated abnormalities may include an impaired ability to completely close the eyes, limited movements of the lips, and difficulties raising the arms over the head. Affected individuals may also eventually develop weakness and associated wasting (atrophy) of muscles of the hips and thighs and/or involvement of lower leg muscles. Although the disease course may be variable, FSHD is most typically characterized by relatively slow disease progression. Specific symptoms and findings may also vary in range and severity, including among affected members of the same family (kindred). FSHD is usually inherited as an autosomal dominant trait. However, in up to approximately 30 percent of affected individuals, there is no apparent family history of the disorder. In some of these cases, FSHD may be due to new genetic changes (mutations) that appear to occur spontaneously for unknown reasons (sporadically). (For more information on this disorder, choose “facioscapulohumeral muscular dystrophy” as your search term in the Rare Disease Database.)Emery-Dreifuss muscular dystrophy (EDMD) is a rare, often slowly progressive form of muscular dystrophy affecting the muscles of the arms, legs, face, neck, spine and heart. The disorder consists of weakness and degeneration of certain muscles, joints that are fixed in a flexed or extended position (contractures), and abnormalities affecting the heart (cardiomyopathy). Major symptoms may include muscle wasting and weakness particularly in the upper legs and arms and contractures of the elbows, Achilles tendons, and upper back muscles. In some cases, additional abnormalities may be present. In most cases, muscle weakness is slowly progressive. Heart abnormalities can potentially result in life-threatening complications. EDMD is usually inherited as an x-linked recessive trait, but may also be inherited as an autosomal dominant or autosomal recessive trait. Autosomal dominant Emery Dreifuss muscular dystrophy is caused by mutations in lamin A/C, the same gene involved in LGMD1B and there may be significant clinical overlaps. (For more information about this condition, choose “Emery Dreifuss” as your search term in the Rare Disease Database.)Spinal muscular atrophy (SMA) that is caused by a deletion of the SMN gene on chromosome 5 is an inherited progressive neuromuscular disorder characterized by degeneration of groups of nerve cells (motor nuclei) within the lowest region of the brain (lower brainstem) and certain motor neurons in the spinal cord (anterior horn cells). Motor neurons are nerve cells that transmit nerve impulses from the spinal cord or brain (central nervous system) to muscle or glandular tissue. Typical symptoms are a slowly progressive muscle weakness and muscle wasting (atrophy). Affected individuals have poor muscle tone, muscle weakness on both sides of the body without, or with minimal, involvement of the face muscles, twitching tongue and a lack of deep tendon reflexes. SMA is divided into subtypes based on age of onset of symptoms and maximum function achieved. (For more information on this disorder, choose “spinal muscular atrophy” as your search term in the Rare Disease Database.)Additional forms of muscle disease (myopathy) are considered differential diagnoses for LGMD including metabolic myopathies such as Pompe disease; inflammatory myopathies such as dermatomyositis or polymyositis; and distinct congenital myopathies such as nemaline myopathy. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Limb-Girdle Muscular Dystrophies
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Diagnosis of Limb-Girdle Muscular Dystrophies
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Within the LGMD group, it is important to reach a precise diagnosis so that the patient and his or her family may be given correct genetic advice, as well as appropriate guidance for the management of complications, which can vary from disease entity to disease entity. This particularly relates to the risk of cardiac or respiratory complications. The precise testing available today may make it possible for individuals who were given a presumed diagnosis of LGMD in the past to be reappraised and given a more precise molecular diagnosis.A diagnosis of LGMD is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms (e.g., specific distribution of muscle weakness and atrophy), and a variety of specialized tests including surgical removal and microscopic examination (biopsy) of affected muscle tissue that may reveal characteristic changes to muscle fibers; a test that assesses the health of muscles and the nerves that control muscles (electromyography); specialized blood tests; tests that evaluate the presence and number of certain muscle proteins (immunohistochemistry); and molecular genetic testing.During an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy and also neuromuscular junction disorders such as myasthenic syndromes some of which may present with limb girdle weakness. It will not allow the diagnosis of a specific LGMD subtype but can be useful to exclude alternative diagnoses.Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. Elevated CK levels occur in some, but not all cases of LGMD. CK levels are much higher in the autosomal recessive forms of LGMD than the autosomal dominant forms. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of LGMD. It may however help to indicate which type of LGMD is more likely than others.In some cases, a specialized test can be performed on muscle biopsy samples that can determine the presence and levels of specific muscle proteins within muscle cells. Various techniques such as immunostaining, immunofluorescence or Western blot (immunoblot) can be used. These tests involve the use of certain antibodies that react to certain muscle proteins. Tissue samples from muscle biopsies are exposed to these antibodies and the results can determine whether a specific muscle protein is present and in what quantity. Deficiency of certain muscle proteins indicates what form of LGMD is present. These protein tests are not available for all forms of LGMD, but can be used to test for LGMD2C-2F (the sarcoglycanopathies), LGMD1C (caveolinopathy), LGMD2B (dysferlinopathy) and some cases of LGMD2A (calpainopathy).Molecular genetic testing involves the examination of deoxyribonucleic acid (DNA) to identify specific a genetic mutation. This is now the gold standard for diagnosis in LGMD and allows a specific diagnosis as well as specific testing for other family members.A consortium of LGMD foundations created a new diagnostic program housed at http://LGMD-diagnosis.org to offer free genetic sequencing to patients with limb-girdle muscle weakness. LGMD-diagnosis offers an online quiz that individuals without a genetic explanation for their muscle weakness can take to determine whether they are eligible for free genetic sequencing. Physicians may also apply on behalf of their patients by using the Automated LGMD Diagnostic Assistant (ALDA) developed by the Jain Foundation to determine whether their patients qualify.
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Diagnosis of Limb-Girdle Muscular Dystrophies. Within the LGMD group, it is important to reach a precise diagnosis so that the patient and his or her family may be given correct genetic advice, as well as appropriate guidance for the management of complications, which can vary from disease entity to disease entity. This particularly relates to the risk of cardiac or respiratory complications. The precise testing available today may make it possible for individuals who were given a presumed diagnosis of LGMD in the past to be reappraised and given a more precise molecular diagnosis.A diagnosis of LGMD is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms (e.g., specific distribution of muscle weakness and atrophy), and a variety of specialized tests including surgical removal and microscopic examination (biopsy) of affected muscle tissue that may reveal characteristic changes to muscle fibers; a test that assesses the health of muscles and the nerves that control muscles (electromyography); specialized blood tests; tests that evaluate the presence and number of certain muscle proteins (immunohistochemistry); and molecular genetic testing.During an electromyography, a needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to the nerves and can determine whether muscle weakness is caused by the muscle themselves or by the nerves that control the muscles. An electromyography can rule out nerve disorders such as motor neuron disease and peripheral neuropathy and also neuromuscular junction disorders such as myasthenic syndromes some of which may present with limb girdle weakness. It will not allow the diagnosis of a specific LGMD subtype but can be useful to exclude alternative diagnoses.Blood tests may reveal elevated levels of the creatine kinase (CK), an enzyme that is often found in abnormally high levels when muscle is damaged. Elevated CK levels occur in some, but not all cases of LGMD. CK levels are much higher in the autosomal recessive forms of LGMD than the autosomal dominant forms. The detection of elevated CK levels can confirm that muscle is damaged or inflamed, but cannot confirm a diagnosis of LGMD. It may however help to indicate which type of LGMD is more likely than others.In some cases, a specialized test can be performed on muscle biopsy samples that can determine the presence and levels of specific muscle proteins within muscle cells. Various techniques such as immunostaining, immunofluorescence or Western blot (immunoblot) can be used. These tests involve the use of certain antibodies that react to certain muscle proteins. Tissue samples from muscle biopsies are exposed to these antibodies and the results can determine whether a specific muscle protein is present and in what quantity. Deficiency of certain muscle proteins indicates what form of LGMD is present. These protein tests are not available for all forms of LGMD, but can be used to test for LGMD2C-2F (the sarcoglycanopathies), LGMD1C (caveolinopathy), LGMD2B (dysferlinopathy) and some cases of LGMD2A (calpainopathy).Molecular genetic testing involves the examination of deoxyribonucleic acid (DNA) to identify specific a genetic mutation. This is now the gold standard for diagnosis in LGMD and allows a specific diagnosis as well as specific testing for other family members.A consortium of LGMD foundations created a new diagnostic program housed at http://LGMD-diagnosis.org to offer free genetic sequencing to patients with limb-girdle muscle weakness. LGMD-diagnosis offers an online quiz that individuals without a genetic explanation for their muscle weakness can take to determine whether they are eligible for free genetic sequencing. Physicians may also apply on behalf of their patients by using the Automated LGMD Diagnostic Assistant (ALDA) developed by the Jain Foundation to determine whether their patients qualify.
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Limb-Girdle Muscular Dystrophies
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Therapies of Limb-Girdle Muscular Dystrophies
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TreatmentNo cure exists for any form of LGMD. Treatment is aimed at the specific symptoms present in each individual. Specific treatment options may include physical and occupational therapy to improve muscle strength and prevent contractures; the use of various devices (e.g., canes, braces, walkers, wheelchairs) to assist with walking (ambulation) and mobility; surgery to correct skeletal abnormalities such as scoliosis; and regular monitoring of the heart and the respiratory system for the development of such complications potentially associated with some forms of LGMD.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. Patients should be provided with contact details for the relevant patient organizations and registries.
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Therapies of Limb-Girdle Muscular Dystrophies. TreatmentNo cure exists for any form of LGMD. Treatment is aimed at the specific symptoms present in each individual. Specific treatment options may include physical and occupational therapy to improve muscle strength and prevent contractures; the use of various devices (e.g., canes, braces, walkers, wheelchairs) to assist with walking (ambulation) and mobility; surgery to correct skeletal abnormalities such as scoliosis; and regular monitoring of the heart and the respiratory system for the development of such complications potentially associated with some forms of LGMD.Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive. Patients should be provided with contact details for the relevant patient organizations and registries.
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Limb-Girdle Muscular Dystrophies
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Overview of Liposarcoma
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SummaryLiposarcoma is a rare tumor derived from fat tissue that occurs in the “soft tissues” of the body (soft tissue sarcoma). It is classified as a cancer (malignant) because of its potential to recur locally and spread to other areas of the body. The severity of disease depends on the subtype of the liposarcoma and the presenting stage of the primary tumor. It can arise in various locations throughout the body, although it is most frequently found in the extremities particularly in the thigh. It can also grow in the back of the abdomen in an area called the “retroperitoneum” where, because of the vast amount of space, can effectively hide a tumor of substantial size and weight. Some individuals with liposarcoma may not have symptoms in the early stages, but as the tumor grows and advances to later stages, it can potentially compress other tissues and cause pain. The specific genetic cause of liposarcoma has yet to be identified, though studies have proposed that it starts in fat cells that have lost their ability to mature or have unregulated growth. It has been found to be more common in middle-aged males from 50 – 65 years of age compared to females and is very rare in children. The mainstay of treatment is surgery or chemotherapy/radiation depending on the staging of the tumor at presentation.
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Overview of Liposarcoma. SummaryLiposarcoma is a rare tumor derived from fat tissue that occurs in the “soft tissues” of the body (soft tissue sarcoma). It is classified as a cancer (malignant) because of its potential to recur locally and spread to other areas of the body. The severity of disease depends on the subtype of the liposarcoma and the presenting stage of the primary tumor. It can arise in various locations throughout the body, although it is most frequently found in the extremities particularly in the thigh. It can also grow in the back of the abdomen in an area called the “retroperitoneum” where, because of the vast amount of space, can effectively hide a tumor of substantial size and weight. Some individuals with liposarcoma may not have symptoms in the early stages, but as the tumor grows and advances to later stages, it can potentially compress other tissues and cause pain. The specific genetic cause of liposarcoma has yet to be identified, though studies have proposed that it starts in fat cells that have lost their ability to mature or have unregulated growth. It has been found to be more common in middle-aged males from 50 – 65 years of age compared to females and is very rare in children. The mainstay of treatment is surgery or chemotherapy/radiation depending on the staging of the tumor at presentation.
| 727 |
Liposarcoma
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Symptoms of Liposarcoma
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As previously mentioned, most patients who are diagnosed with liposarcoma do not have any early symptoms and it can go unnoticed during the initial stages of the disease until the tumor has grown to a large enough size to compress neighboring tissues and cause pain or decreased function. It can sometimes be noticed as a deep-seated mass to touch. Liposarcoma, as with all other cancers, can present with non-specific symptoms such as fevers, chills, fatigue, night sweats and weight loss. If the tumor is retroperitoneal in location, it can present with specific symptoms in the abdomen, including abdominal or flank pain, swelling, and constipation or the sensation of feeling full sooner than expected after eating.There are five subtypes of liposarcoma: well differentiated, dedifferentiated, myxoid, round cell and pleomorphic. The well differentiated type is less aggressive and tends to be a large painless mass found in deeper tissues and in the retroperitoneum. Myxoid, round cell and pleomorphic types tend to be in the arms and legs, whereas dedifferentiated tends to be in the retroperitoneum and often associated with the well differentiated variety. Specifically, pleomorphic liposarcoma is the least common subtype with a high rate of recurrence and poor outcomes.
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Symptoms of Liposarcoma. As previously mentioned, most patients who are diagnosed with liposarcoma do not have any early symptoms and it can go unnoticed during the initial stages of the disease until the tumor has grown to a large enough size to compress neighboring tissues and cause pain or decreased function. It can sometimes be noticed as a deep-seated mass to touch. Liposarcoma, as with all other cancers, can present with non-specific symptoms such as fevers, chills, fatigue, night sweats and weight loss. If the tumor is retroperitoneal in location, it can present with specific symptoms in the abdomen, including abdominal or flank pain, swelling, and constipation or the sensation of feeling full sooner than expected after eating.There are five subtypes of liposarcoma: well differentiated, dedifferentiated, myxoid, round cell and pleomorphic. The well differentiated type is less aggressive and tends to be a large painless mass found in deeper tissues and in the retroperitoneum. Myxoid, round cell and pleomorphic types tend to be in the arms and legs, whereas dedifferentiated tends to be in the retroperitoneum and often associated with the well differentiated variety. Specifically, pleomorphic liposarcoma is the least common subtype with a high rate of recurrence and poor outcomes.
| 727 |
Liposarcoma
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Causes of Liposarcoma
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The specific cause of liposarcoma is still unknown. Clinically, it can be first noticed particularly in the extremity in an area of recent trauma where the patient may find a mass, however the cause and effect are quite likely purely coincidental. Liposarcoma generally is attributed to a change in some of the genes that are normally present in fat cells. A series of abnormalities in these genes (mutations or DNA alterations) can lead to malignant changes characterized by uncontrollable growth.
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Causes of Liposarcoma. The specific cause of liposarcoma is still unknown. Clinically, it can be first noticed particularly in the extremity in an area of recent trauma where the patient may find a mass, however the cause and effect are quite likely purely coincidental. Liposarcoma generally is attributed to a change in some of the genes that are normally present in fat cells. A series of abnormalities in these genes (mutations or DNA alterations) can lead to malignant changes characterized by uncontrollable growth.
| 727 |
Liposarcoma
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Affects of Liposarcoma
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Liposarcoma is a soft tissue sarcoma, affecting approximately 2000 individuals each year in the United States. It affects men more than women, and more specifically middle-aged men ranging from 50 – 65 years of age. Children are rarely diagnosed, but when liposarcoma does occur in children, it is usually during adolescence. There is no specific ethnicity in which liposarcoma is more common. Certain risk factors have been shown to predispose individuals to developing soft tissue sarcomas, such as liposarcoma, including prior radiation, familial cancer syndromes, damage to the lymph system, and long-term exposure to certain toxic chemicals such as vinyl chloride, a chemical used to make plastic.
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Affects of Liposarcoma. Liposarcoma is a soft tissue sarcoma, affecting approximately 2000 individuals each year in the United States. It affects men more than women, and more specifically middle-aged men ranging from 50 – 65 years of age. Children are rarely diagnosed, but when liposarcoma does occur in children, it is usually during adolescence. There is no specific ethnicity in which liposarcoma is more common. Certain risk factors have been shown to predispose individuals to developing soft tissue sarcomas, such as liposarcoma, including prior radiation, familial cancer syndromes, damage to the lymph system, and long-term exposure to certain toxic chemicals such as vinyl chloride, a chemical used to make plastic.
| 727 |
Liposarcoma
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Related disorders of Liposarcoma
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There are other diseases that can present very similarly to liposarcoma. Lipoma is a non-cancerous (benign) tumor that can look like liposarcoma, but it is usually softer and feels like a mass directly below the skin rather than in deeper parts of the body. A lipoma cannot transform into a liposarcoma. Other soft tissue tumors, such as undifferentiated pleomorphic sarcoma, lipomatous hemangiopericytoma, non-lipogenic sarcoma and gastrointestinal stromal tumors, can also look like liposarcoma when initially evaluated under a microscope.
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Related disorders of Liposarcoma. There are other diseases that can present very similarly to liposarcoma. Lipoma is a non-cancerous (benign) tumor that can look like liposarcoma, but it is usually softer and feels like a mass directly below the skin rather than in deeper parts of the body. A lipoma cannot transform into a liposarcoma. Other soft tissue tumors, such as undifferentiated pleomorphic sarcoma, lipomatous hemangiopericytoma, non-lipogenic sarcoma and gastrointestinal stromal tumors, can also look like liposarcoma when initially evaluated under a microscope.
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Liposarcoma
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Diagnosis of Liposarcoma
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The most critical step in the diagnosis of liposarcoma involves taking a biopsy of the mass of concern. A biopsy is when tissue is retrieved from the tumor in order to be evaluated under the microscope to assess whether or not the tissue has tumor-specific features. Since many of these tumors are deeply embedded into the body, imaging such as ultrasound can be used to guide where the needle is relative to the mass and ensure that the tissue sample is retrieved specifically from that mass.Liposarcoma can also be diagnosed by imaging the body either by computed tomography (CT) or magnetic resonance imaging (MRI). CT uses multiple X-ray measurements to create an image of the body and it is important in assessing the location of a mass and its relationship to surrounding tissues. MRI is another way to image liposarcoma, and it can show characteristics of the mass itself which might be helpful in diagnostic differences between benign and malignant soft tissue masses.
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Diagnosis of Liposarcoma. The most critical step in the diagnosis of liposarcoma involves taking a biopsy of the mass of concern. A biopsy is when tissue is retrieved from the tumor in order to be evaluated under the microscope to assess whether or not the tissue has tumor-specific features. Since many of these tumors are deeply embedded into the body, imaging such as ultrasound can be used to guide where the needle is relative to the mass and ensure that the tissue sample is retrieved specifically from that mass.Liposarcoma can also be diagnosed by imaging the body either by computed tomography (CT) or magnetic resonance imaging (MRI). CT uses multiple X-ray measurements to create an image of the body and it is important in assessing the location of a mass and its relationship to surrounding tissues. MRI is another way to image liposarcoma, and it can show characteristics of the mass itself which might be helpful in diagnostic differences between benign and malignant soft tissue masses.
| 727 |
Liposarcoma
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Therapies of Liposarcoma
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Treatment
Therapy to treat liposarcoma largely depends on the type, size and location of the tumor. Surgery is a favored option compared to others, but there are certain cases where it would be riskier to attempt to remove the tumor surgically. For example, this can occur if it is in the retroperitoneum where it is deeply embedded and involves multiple organs. Another example would be if the tumor were adjacent to vital structures, such as major blood vessels, where removing the tumor itself could pose a significant risk. If a tumor spreads in such a way that the mass cannot be completely removed with surgery, chemotherapy or radiation therapy can be considered to kill the rest of the tumor and reduce the risk of the cancer reoccurrence. In certain circumstances, chemotherapy and/or radiation therapy prior to surgery can be considered to shrink the tumor to a size where it can be successfully surgically removed.The FDA has approved new therapeutic options to treat tumors that are either widespread or not amendable to surgical removal. Several new chemotherapeutic agents have had some success in liposarcoma management. Erybulin mesylate (Halaven) is administered by injection specifically targets a critical step in cell division that prevents cells from dividing and ultimately kills off tumor cells. Trabectedin (Yondelis) works in a similar manner by interfering with the gene repair mechanism of tumor cells. After treatment, routine follow up will continue on a regular basis with physical exams and imaging studies, such as an MRI or CT to assess for presence of new masses.
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Therapies of Liposarcoma. Treatment
Therapy to treat liposarcoma largely depends on the type, size and location of the tumor. Surgery is a favored option compared to others, but there are certain cases where it would be riskier to attempt to remove the tumor surgically. For example, this can occur if it is in the retroperitoneum where it is deeply embedded and involves multiple organs. Another example would be if the tumor were adjacent to vital structures, such as major blood vessels, where removing the tumor itself could pose a significant risk. If a tumor spreads in such a way that the mass cannot be completely removed with surgery, chemotherapy or radiation therapy can be considered to kill the rest of the tumor and reduce the risk of the cancer reoccurrence. In certain circumstances, chemotherapy and/or radiation therapy prior to surgery can be considered to shrink the tumor to a size where it can be successfully surgically removed.The FDA has approved new therapeutic options to treat tumors that are either widespread or not amendable to surgical removal. Several new chemotherapeutic agents have had some success in liposarcoma management. Erybulin mesylate (Halaven) is administered by injection specifically targets a critical step in cell division that prevents cells from dividing and ultimately kills off tumor cells. Trabectedin (Yondelis) works in a similar manner by interfering with the gene repair mechanism of tumor cells. After treatment, routine follow up will continue on a regular basis with physical exams and imaging studies, such as an MRI or CT to assess for presence of new masses.
| 727 |
Liposarcoma
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Overview of Lissencephaly
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SummaryLissencephaly type 1, also known as classic lissencephaly, is a brain malformation that may occur as an isolated abnormality (isolated lissencephaly sequence [ILS]) or in association with certain syndromes (e.g., Miller-Dieker syndrome). The condition is characterized by agyria or pachygyria, which means absence or incomplete development, respectively, of the brain gyri or convolution, causing the brain's surface to appear unusually smooth.Infants with classical lissencephaly may have a head that is smaller than would be expected (microcephalic). Additional abnormalities may include seizures, profound intellectual disability, feeding difficulties, growth retardation, and impaired motor abilities. If an underlying syndrome is present, there may be additional symptoms and physical findings.There may be various possible causes of isolated lissencephaly, including viral infections, insufficient blood flow to the brain during development, or certain genetic factors. Changes (mutations) in several genes have been implicated in isolated lissencephaly: LIS1, RELN, TUBA1A, NDE1, KATNB1, CDK5, ARX and DCX. Of these, LIS1 and DCX gene mutations have been most studied.
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Overview of Lissencephaly. SummaryLissencephaly type 1, also known as classic lissencephaly, is a brain malformation that may occur as an isolated abnormality (isolated lissencephaly sequence [ILS]) or in association with certain syndromes (e.g., Miller-Dieker syndrome). The condition is characterized by agyria or pachygyria, which means absence or incomplete development, respectively, of the brain gyri or convolution, causing the brain's surface to appear unusually smooth.Infants with classical lissencephaly may have a head that is smaller than would be expected (microcephalic). Additional abnormalities may include seizures, profound intellectual disability, feeding difficulties, growth retardation, and impaired motor abilities. If an underlying syndrome is present, there may be additional symptoms and physical findings.There may be various possible causes of isolated lissencephaly, including viral infections, insufficient blood flow to the brain during development, or certain genetic factors. Changes (mutations) in several genes have been implicated in isolated lissencephaly: LIS1, RELN, TUBA1A, NDE1, KATNB1, CDK5, ARX and DCX. Of these, LIS1 and DCX gene mutations have been most studied.
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Lissencephaly
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Symptoms of Lissencephaly
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Newborns with lissencephaly type 1 who have no underlying syndrome are said to have isolated lissencephaly sequence (ILS). In addition to lissencephaly, those with the condition may have other associated brain malformations, such as absence or underdevelopment of the corpus callosum, which is the thick band of nerve fibers that join and carry messages between the brain’s two cerebral hemispheres. Affected infants often also have microcephaly, seizures, and severe or profound intellectual disability. In addition, those with the condition may have a normal facial appearance or subtle facial changes, such as a relatively small jaw (micrognathia) or a slight indentation of the temples (bitemporal hollowing). Additional symptoms and findings may include feeding difficulties, growth failure, abnormally diminished muscle tone (hypotonia) early in life, and increased muscle tone (hypertonia) later during infancy, and impaired motor abilities.Lissencephaly type 1 also occurs in association with genetic syndromes, including Miller-Dieker syndrome and Norman-Roberts syndrome. In addition to signs and symptoms of classical lissencephaly, infants with Miller-Dieker syndrome may also malformations including microcephaly with a broad, high forehead; bitemporal hollowing; a relatively wide face; micrognathia; a long, thin upper lip; a short nose with upturned nostrils; low-set, malformed ears; polydactyly; abnormal palmar creases; cataracts and/or malformations of the heart, kidneys and/or other organs.Norman-Roberts syndrome is also characterized by lissencephaly type 1 features with certain craniofacial abnormalities, such as a low, sloping forehead; abnormal prominence of the back portion of the head; a broad, prominent nasal bridge; and widely set eyes (ocular hyperterlorism).
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Symptoms of Lissencephaly. Newborns with lissencephaly type 1 who have no underlying syndrome are said to have isolated lissencephaly sequence (ILS). In addition to lissencephaly, those with the condition may have other associated brain malformations, such as absence or underdevelopment of the corpus callosum, which is the thick band of nerve fibers that join and carry messages between the brain’s two cerebral hemispheres. Affected infants often also have microcephaly, seizures, and severe or profound intellectual disability. In addition, those with the condition may have a normal facial appearance or subtle facial changes, such as a relatively small jaw (micrognathia) or a slight indentation of the temples (bitemporal hollowing). Additional symptoms and findings may include feeding difficulties, growth failure, abnormally diminished muscle tone (hypotonia) early in life, and increased muscle tone (hypertonia) later during infancy, and impaired motor abilities.Lissencephaly type 1 also occurs in association with genetic syndromes, including Miller-Dieker syndrome and Norman-Roberts syndrome. In addition to signs and symptoms of classical lissencephaly, infants with Miller-Dieker syndrome may also malformations including microcephaly with a broad, high forehead; bitemporal hollowing; a relatively wide face; micrognathia; a long, thin upper lip; a short nose with upturned nostrils; low-set, malformed ears; polydactyly; abnormal palmar creases; cataracts and/or malformations of the heart, kidneys and/or other organs.Norman-Roberts syndrome is also characterized by lissencephaly type 1 features with certain craniofacial abnormalities, such as a low, sloping forehead; abnormal prominence of the back portion of the head; a broad, prominent nasal bridge; and widely set eyes (ocular hyperterlorism).
| 728 |
Lissencephaly
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Causes of Lissencephaly
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Lissencephaly may be due to various non-genetic and genetic factors. Such factors may include intrauterine infection, insufficient supply of oxygenated blood to the brain (ischemia) during fetal development, and/or different gene mutations.Several gene mutations have been implicated in isolated lissencephaly. One of the best-studied examples is LIS1 or PAFAH1B1. Mutations in this gene are responsible for lissencephaly type 1. LIS1 gene is localized on chromosome 17p13.3. The gene encodes for platelet-activating factor acetylhydrolase isoform 1B that interacts with microtubule associated proteins: dynein and dynactin. This interaction is critical for proper neuronal migration during fetal brain development; disruption of this interaction results in lissencephaly. Most infants with isolated lissencephaly sequence show mutations or deletions of just the LIS1 gene, whereas infants with Miller-Dieker syndrome are mostly found to have mutations in the LIS1 gene but also have additional deletions of adjacent genes on chromosome 17, thus resulting in lissencephaly type 1 features and other craniofacial abnormalities. Such chromosomal alterations occur randomly and are observed in the child only, without evidence of alteration in either parent. Importantly, this genetic form of lissencephaly does not recur in families, and so the risk of another child with this condition is extremely low.Of the genes that have been implicated in lissencephaly, DCX and ARX genes are notable because they are localized on the X chromosome. This genetic form of lissencephaly can be observed in more than one child per family, because the mutation can be present in the DNA of a healthy mother. Lissencephaly caused by DCX and ARX is referred to as X-linked lissencephaly type 1 and 2, respectively (XLIS 1-2 or LISX 1-2). Because males only have one X chromosome, males who inherit the disease gene are more likely to manifest the full spectrum of abnormalities associated with the disorder and therefore are usually more severely affected. Females who inherit this gene mutation may have a more variable presentation and be more mildly affected than the males, or can be healthy without symptoms.The DCX gene encodes for the doublecortin protein. Doublecortin associates with microtubules to regulate neuronal migration. X-linked mutations may appear randomly or can be inherited. The ARX gene encodes for the aristaless-related homeobox protein. In addition to classic lissencephaly features, infants with a ARX mutation may also have absence of portions of the brain (hydranencephaly), abnormal genitalia, severe epilepsy and other abnormalities.Other gene mutations that have been associated with lissencephaly, such as RELN, which causes Norman-Roberts syndrome, have an autosomal recessive inheritance pattern. 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. In addition to LIS1, RELN, DCX and ARX, mutations in other genes have also been found to cause lissencephaly. They include: TUBA1A, NDE1, KATNB1, and CDK5. These genes share molecular function with LIS1 and DCX, working as part of the cellular machinery of dynein and dynactin required for neuronal migration during fetal brain development.Emerging evidence suggests that genetic alterations and non-genetic causes result in lissencephaly due to impaired neuronal migration of the outer region of the brain during fetal development. The cerebral cortex, which is responsible for conscious movement and thought, normally consists of several deep gyri and sulci (grooves), which are formed by “in-folding” of the cerebral cortex. During embryonic growth, newly formed cells that will later develop into specialized nerve cells normally migrate to the brain’s surface (neuronal migration), resulting in the formation of several cellular layers. However, in cases of lissencephaly type 1, the cells fail to migrate to their destined locations resulting in neuronal dysmigration, and the cerebral cortex develops an insufficient number of cellular layers, with absence or incomplete development of gyri.
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Causes of Lissencephaly. Lissencephaly may be due to various non-genetic and genetic factors. Such factors may include intrauterine infection, insufficient supply of oxygenated blood to the brain (ischemia) during fetal development, and/or different gene mutations.Several gene mutations have been implicated in isolated lissencephaly. One of the best-studied examples is LIS1 or PAFAH1B1. Mutations in this gene are responsible for lissencephaly type 1. LIS1 gene is localized on chromosome 17p13.3. The gene encodes for platelet-activating factor acetylhydrolase isoform 1B that interacts with microtubule associated proteins: dynein and dynactin. This interaction is critical for proper neuronal migration during fetal brain development; disruption of this interaction results in lissencephaly. Most infants with isolated lissencephaly sequence show mutations or deletions of just the LIS1 gene, whereas infants with Miller-Dieker syndrome are mostly found to have mutations in the LIS1 gene but also have additional deletions of adjacent genes on chromosome 17, thus resulting in lissencephaly type 1 features and other craniofacial abnormalities. Such chromosomal alterations occur randomly and are observed in the child only, without evidence of alteration in either parent. Importantly, this genetic form of lissencephaly does not recur in families, and so the risk of another child with this condition is extremely low.Of the genes that have been implicated in lissencephaly, DCX and ARX genes are notable because they are localized on the X chromosome. This genetic form of lissencephaly can be observed in more than one child per family, because the mutation can be present in the DNA of a healthy mother. Lissencephaly caused by DCX and ARX is referred to as X-linked lissencephaly type 1 and 2, respectively (XLIS 1-2 or LISX 1-2). Because males only have one X chromosome, males who inherit the disease gene are more likely to manifest the full spectrum of abnormalities associated with the disorder and therefore are usually more severely affected. Females who inherit this gene mutation may have a more variable presentation and be more mildly affected than the males, or can be healthy without symptoms.The DCX gene encodes for the doublecortin protein. Doublecortin associates with microtubules to regulate neuronal migration. X-linked mutations may appear randomly or can be inherited. The ARX gene encodes for the aristaless-related homeobox protein. In addition to classic lissencephaly features, infants with a ARX mutation may also have absence of portions of the brain (hydranencephaly), abnormal genitalia, severe epilepsy and other abnormalities.Other gene mutations that have been associated with lissencephaly, such as RELN, which causes Norman-Roberts syndrome, have an autosomal recessive inheritance pattern. 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. In addition to LIS1, RELN, DCX and ARX, mutations in other genes have also been found to cause lissencephaly. They include: TUBA1A, NDE1, KATNB1, and CDK5. These genes share molecular function with LIS1 and DCX, working as part of the cellular machinery of dynein and dynactin required for neuronal migration during fetal brain development.Emerging evidence suggests that genetic alterations and non-genetic causes result in lissencephaly due to impaired neuronal migration of the outer region of the brain during fetal development. The cerebral cortex, which is responsible for conscious movement and thought, normally consists of several deep gyri and sulci (grooves), which are formed by “in-folding” of the cerebral cortex. During embryonic growth, newly formed cells that will later develop into specialized nerve cells normally migrate to the brain’s surface (neuronal migration), resulting in the formation of several cellular layers. However, in cases of lissencephaly type 1, the cells fail to migrate to their destined locations resulting in neuronal dysmigration, and the cerebral cortex develops an insufficient number of cellular layers, with absence or incomplete development of gyri.
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Lissencephaly
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Affects of Lissencephaly
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The overall incidence of lissencephaly is rare and estimated around 1.2/100,000 births.
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Affects of Lissencephaly. The overall incidence of lissencephaly is rare and estimated around 1.2/100,000 births.
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Lissencephaly
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