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nord_685_5
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Diagnosis of Kohler Disease
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A diagnosis of Kohler disease is suspected based on the presence of the signs of symptoms in the child. The clinical diagnosis of Kohler disease is reinforced by X-rays that show flattening, sclerosis, and fragmentation of the navicular bone, which can be compared to the unaffected side to make the diagnosis. However, these abnormalities of the navicular bone are bilateral in approximately 25% of patients and may be seen in children who do not have Kohler disease.
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Diagnosis of Kohler Disease. A diagnosis of Kohler disease is suspected based on the presence of the signs of symptoms in the child. The clinical diagnosis of Kohler disease is reinforced by X-rays that show flattening, sclerosis, and fragmentation of the navicular bone, which can be compared to the unaffected side to make the diagnosis. However, these abnormalities of the navicular bone are bilateral in approximately 25% of patients and may be seen in children who do not have Kohler disease.
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Kohler Disease
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nord_685_6
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Therapies of Kohler Disease
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Treatment
Kohler disease typically resolves over time with or without treatment. Symptoms can last for a few days or persist for up to two years, but symptoms usually resolve within six months. Treatment can include pain relievers or weight-bearing short-leg plaster casts. Special supportive shoes may also be considered. Staying off the foot as much as possible helps in recovery. The long-term outlook (prognosis) for people with Kohler disease is usually excellent. People affected by the condition typically recover all function of the affected foot and have no lasting consequences.
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Therapies of Kohler Disease. Treatment
Kohler disease typically resolves over time with or without treatment. Symptoms can last for a few days or persist for up to two years, but symptoms usually resolve within six months. Treatment can include pain relievers or weight-bearing short-leg plaster casts. Special supportive shoes may also be considered. Staying off the foot as much as possible helps in recovery. The long-term outlook (prognosis) for people with Kohler disease is usually excellent. People affected by the condition typically recover all function of the affected foot and have no lasting consequences.
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Kohler Disease
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nord_686_0
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Overview of Koolen-de Vries Syndrome
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Koolen-de Vries syndrome (KdVS) is a rare genetic disorder with an estimated prevalence of about 1 in 30,000 people. Frequent features in individuals with this condition include feeding problems in infancy, muscle weakness (hypotonia) in young children, developmental problems, language/speech delay, learning disabilities and mild to moderate intellectual disability, epilepsy (in about 1 in 3 persons), characteristic facial features, farsightedness, hearing impairment, flexible joints, flat feet and curvature of the spine and/or congenital abnormalities.Affected children and adults are often sociable and friendly, but behavior problems such as hyperactivity and compulsive behavior may also be present. Some children with KdVS have birth defects. In a significant portion of boys for instance, the testes have not descended (cryptorchidism). Hip dysplasia is more common as well and some of the children have congenital heart defects (particularly atrial septal defect and ventricular septal defect), abnormalities of the bladder and urinary tract and/or brain. Koolen-de Vries syndrome is caused by deletion or change (pathogenic variant) in the KANSL1 gene. Introduction The 17q21.31 microdeletion syndrome was discovered in 2006 by three independent research groups. In 2012, it was established that KANSL1 was the causative gene for KdVS. The syndrome is named after Dutch geneticists David A. Koolen and Bert B. A. de Vries, who helped discover the syndrome in 2006 and the KANSL1 gene in 2012.
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Overview of Koolen-de Vries Syndrome. Koolen-de Vries syndrome (KdVS) is a rare genetic disorder with an estimated prevalence of about 1 in 30,000 people. Frequent features in individuals with this condition include feeding problems in infancy, muscle weakness (hypotonia) in young children, developmental problems, language/speech delay, learning disabilities and mild to moderate intellectual disability, epilepsy (in about 1 in 3 persons), characteristic facial features, farsightedness, hearing impairment, flexible joints, flat feet and curvature of the spine and/or congenital abnormalities.Affected children and adults are often sociable and friendly, but behavior problems such as hyperactivity and compulsive behavior may also be present. Some children with KdVS have birth defects. In a significant portion of boys for instance, the testes have not descended (cryptorchidism). Hip dysplasia is more common as well and some of the children have congenital heart defects (particularly atrial septal defect and ventricular septal defect), abnormalities of the bladder and urinary tract and/or brain. Koolen-de Vries syndrome is caused by deletion or change (pathogenic variant) in the KANSL1 gene. Introduction The 17q21.31 microdeletion syndrome was discovered in 2006 by three independent research groups. In 2012, it was established that KANSL1 was the causative gene for KdVS. The syndrome is named after Dutch geneticists David A. Koolen and Bert B. A. de Vries, who helped discover the syndrome in 2006 and the KANSL1 gene in 2012.
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Koolen-de Vries Syndrome
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nord_686_1
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Symptoms of Koolen-de Vries Syndrome
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KdVS is associated with a broad spectrum of symptoms that vary greatly from person to person. Some individuals are more affected than others and an individual with KdVS will not have all the symptoms mentioned in this section. For instance, most will learn to speak at a later age, while some may not speak at all.Symptoms like developmental delay and/or intellectual disability are very common and present in almost all of individuals with KdVS. This includes speech and language delay which is present in almost all individuals. Children with KdVS usually do learn to speak, but at a significantly later age. The first words occur between ages 2.5 and 3.5 years on average. Sign language or communication devices can help promote communication development and communication in general. Usually however, speech development improves significantly around age 8 to 12 years. Stuttering has been described in some individuals, but not in most. In most individuals, behavior is described as friendly, amiable and cooperative. However, behavior problems, including attention-deficit/hyperactivity disorder and autism have been reported.Low muscle tone and specific facial features that can be recognized by a medical expert are very common as well. The nose can have a high nasal bridge, broad nasal root, long columella and underdeveloped and/or thick alae nasi. The facial characteristics change with age. In infancy the facial gestalt is mostly characterized by low muscle tone with an open mouth appearance. With increasing age there is usually elongation of the face and broadening of the chin and the “tubular” or “pear” shape form of the nose may become more apparent.Low muscle tone can be evident from a very young age, along with poor sucking and feeding problems. Some newborns may require hospitalization and/or tube feeding. When they get older, many children with KdVS have problems chewing lumpy or solid textures.Epilepsy is a relatively common symptom in individuals with KdVS, affecting about a third of individuals. Seizures usually start in childhood, presenting with a typical pattern when measuring brain activity. The seizures are sometimes related to structural abnormalities of the brain, but not always and generally respond well to anti-epileptic drugs.Other common symptoms include visual problems including far-sightedness, strabismus or cataracts. Congenital abnormalities in the heart or kidney may also be present. These include, but are not limited to, a heart abnormality in which there is a hole in the wall that separates the lower or upper chambers or a widened aorta (the main and largest artery in the human body). During puberty and thereafter, some individuals develop a curved spine (scoliosis) that requires treatment.Finally, there is a wide range of symptoms described more frequently in individuals with KdVS than in healthy individuals but are not very common. These include dental anomalies, a slender build, fair hair and multiple birthmarks.
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Symptoms of Koolen-de Vries Syndrome. KdVS is associated with a broad spectrum of symptoms that vary greatly from person to person. Some individuals are more affected than others and an individual with KdVS will not have all the symptoms mentioned in this section. For instance, most will learn to speak at a later age, while some may not speak at all.Symptoms like developmental delay and/or intellectual disability are very common and present in almost all of individuals with KdVS. This includes speech and language delay which is present in almost all individuals. Children with KdVS usually do learn to speak, but at a significantly later age. The first words occur between ages 2.5 and 3.5 years on average. Sign language or communication devices can help promote communication development and communication in general. Usually however, speech development improves significantly around age 8 to 12 years. Stuttering has been described in some individuals, but not in most. In most individuals, behavior is described as friendly, amiable and cooperative. However, behavior problems, including attention-deficit/hyperactivity disorder and autism have been reported.Low muscle tone and specific facial features that can be recognized by a medical expert are very common as well. The nose can have a high nasal bridge, broad nasal root, long columella and underdeveloped and/or thick alae nasi. The facial characteristics change with age. In infancy the facial gestalt is mostly characterized by low muscle tone with an open mouth appearance. With increasing age there is usually elongation of the face and broadening of the chin and the “tubular” or “pear” shape form of the nose may become more apparent.Low muscle tone can be evident from a very young age, along with poor sucking and feeding problems. Some newborns may require hospitalization and/or tube feeding. When they get older, many children with KdVS have problems chewing lumpy or solid textures.Epilepsy is a relatively common symptom in individuals with KdVS, affecting about a third of individuals. Seizures usually start in childhood, presenting with a typical pattern when measuring brain activity. The seizures are sometimes related to structural abnormalities of the brain, but not always and generally respond well to anti-epileptic drugs.Other common symptoms include visual problems including far-sightedness, strabismus or cataracts. Congenital abnormalities in the heart or kidney may also be present. These include, but are not limited to, a heart abnormality in which there is a hole in the wall that separates the lower or upper chambers or a widened aorta (the main and largest artery in the human body). During puberty and thereafter, some individuals develop a curved spine (scoliosis) that requires treatment.Finally, there is a wide range of symptoms described more frequently in individuals with KdVS than in healthy individuals but are not very common. These include dental anomalies, a slender build, fair hair and multiple birthmarks.
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Koolen-de Vries Syndrome
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nord_686_2
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Causes of Koolen-de Vries Syndrome
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KdVS is caused by a deletion of a small part of chromosome 17 or by a change (pathogenic variant) in the KANSL1 gene. Chromosomes are the carriers of the genetic information and are important for directing and regulating all processes in the body. The part of chromosome 17 that is missing in many people with KdVS is denoted by “q21.31”. The missing portion of the hereditary material is called a “deletion”. Because this small deletion is not visible with older techniques, the syndrome was first known as a “17q21.31 microdeletion”. Until 2012, KdVS was called the 17q21.31 microdeletion syndrome, but in 2012 it was discovered that variants in the KANSL1 gene (one of the genes in the 17q21.31 region) can lead to the KdVS. This is the reason the condition was renamed. There is no relationship between the size of the deletion and the degree of symptoms. Furthermore, there is no clinical difference between persons with a 17q21.31 deletion and a KANSL1 pathogenic variant.KdVS follows autosomal dominant inheritance. 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. In people with KdVS, the mutated gene is typically a new (de novo) gene variant. 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 Koolen-de Vries Syndrome. KdVS is caused by a deletion of a small part of chromosome 17 or by a change (pathogenic variant) in the KANSL1 gene. Chromosomes are the carriers of the genetic information and are important for directing and regulating all processes in the body. The part of chromosome 17 that is missing in many people with KdVS is denoted by “q21.31”. The missing portion of the hereditary material is called a “deletion”. Because this small deletion is not visible with older techniques, the syndrome was first known as a “17q21.31 microdeletion”. Until 2012, KdVS was called the 17q21.31 microdeletion syndrome, but in 2012 it was discovered that variants in the KANSL1 gene (one of the genes in the 17q21.31 region) can lead to the KdVS. This is the reason the condition was renamed. There is no relationship between the size of the deletion and the degree of symptoms. Furthermore, there is no clinical difference between persons with a 17q21.31 deletion and a KANSL1 pathogenic variant.KdVS follows autosomal dominant inheritance. 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. In people with KdVS, the mutated gene is typically a new (de novo) gene variant. 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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Koolen-de Vries Syndrome
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nord_686_3
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Affects of Koolen-de Vries Syndrome
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The prevalence of Koolen-de Vries syndrome is unknown. The estimated prevalence of the 17q21.31 deletion is 1 in 30,000 individuals. Preliminary data suggest that pathogenic variants in the KANSL1 gene may be as frequent as the microdeletions, but more studies are needed to determine an unbiased prevalence. Koolen-de Vries syndrome occurs with equal frequency in males and females.
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Affects of Koolen-de Vries Syndrome. The prevalence of Koolen-de Vries syndrome is unknown. The estimated prevalence of the 17q21.31 deletion is 1 in 30,000 individuals. Preliminary data suggest that pathogenic variants in the KANSL1 gene may be as frequent as the microdeletions, but more studies are needed to determine an unbiased prevalence. Koolen-de Vries syndrome occurs with equal frequency in males and females.
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Koolen-de Vries Syndrome
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nord_686_4
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Related disorders of Koolen-de Vries Syndrome
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There are other conditions with symptoms similar to KdVS. Conditions that might be included in a differential diagnosis include 22q11.2 deletion syndrome, Prader-Willi syndrome, fragile X syndrome, Angelman syndrome and cardiofaciocutaneous syndrome.For more information about these disorders, search for them in the Rare Disease Database.
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Related disorders of Koolen-de Vries Syndrome. There are other conditions with symptoms similar to KdVS. Conditions that might be included in a differential diagnosis include 22q11.2 deletion syndrome, Prader-Willi syndrome, fragile X syndrome, Angelman syndrome and cardiofaciocutaneous syndrome.For more information about these disorders, search for them in the Rare Disease Database.
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Koolen-de Vries Syndrome
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nord_686_5
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Diagnosis of Koolen-de Vries Syndrome
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Koolen-de Vries syndrome can be diagnosed in an individual with the typical symptoms described above and either of the following genetic abnormalities:
A (micro) deletion at chromosome 17 that includes the KANSL1 gene. This is the case for approximately 75% of individuals currently diagnosed with KdVS.A pathogenic variant that causes the KANSL1 gene to not function normally. This is the case in approximately 25% of individuals currently diagnosed with KdVS.
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Diagnosis of Koolen-de Vries Syndrome. Koolen-de Vries syndrome can be diagnosed in an individual with the typical symptoms described above and either of the following genetic abnormalities:
A (micro) deletion at chromosome 17 that includes the KANSL1 gene. This is the case for approximately 75% of individuals currently diagnosed with KdVS.A pathogenic variant that causes the KANSL1 gene to not function normally. This is the case in approximately 25% of individuals currently diagnosed with KdVS.
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Koolen-de Vries Syndrome
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nord_686_6
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Therapies of Koolen-de Vries Syndrome
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Treatment Currently, no treatment for KdVS is available. However, most of the symptoms can be treated, so the quality of life for individuals with KdVS can be improved. First and foremost, it is important that children with KdVS are regularly seen by a pediatrician. The pediatrician can assess the seriousness of the symptoms, such as the degree of developmental delay, nutritional problems, language development and possible visual-hearing problems. Imaging of the heart, bladder and urinary tract is recommended to determine if congenital anomalies are present. The position of the feet and spine should be monitored. Some people with KdVS have been reported with deviations of the feet (particularly flat feet) and a spine that becomes curved, especially lateral curvature (scoliosis). Children with epilepsy should also be followed by a neurologist. Individuals with low muscle tone and obvious language/speech delay should receive intensive supervision by a speech therapist.
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Therapies of Koolen-de Vries Syndrome. Treatment Currently, no treatment for KdVS is available. However, most of the symptoms can be treated, so the quality of life for individuals with KdVS can be improved. First and foremost, it is important that children with KdVS are regularly seen by a pediatrician. The pediatrician can assess the seriousness of the symptoms, such as the degree of developmental delay, nutritional problems, language development and possible visual-hearing problems. Imaging of the heart, bladder and urinary tract is recommended to determine if congenital anomalies are present. The position of the feet and spine should be monitored. Some people with KdVS have been reported with deviations of the feet (particularly flat feet) and a spine that becomes curved, especially lateral curvature (scoliosis). Children with epilepsy should also be followed by a neurologist. Individuals with low muscle tone and obvious language/speech delay should receive intensive supervision by a speech therapist.
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Koolen-de Vries Syndrome
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nord_687_0
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Overview of Kufor Rakeb Syndrome
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SummaryKufor Rakeb syndrome (KRS), also known as Parkinson’s disease 9, is a very rare form of inherited juvenile-onset Parkinson’s disease. Typical (idiopathic) Parkinson’s disease usually affects people aged 60 or over, but individuals affected by KRS will usually start to develop symptoms before 20 years of age. Depending on the individual, symptoms can include typical Parkinson’s disease symptoms (parkinsonism), such as slowed movements (bradykinesia), rigidity, and tremor, as well as other symptoms that are not typically associated with Parkinson’s disease, including partial or complete paralysis of the legs (paraplegia), inability to move the eyes upward (supranuclear upgaze palsy), and loss of coordination of movements (ataxia). Affected individuals also have brain atrophy (cerebral atrophy) and sometimes have an accumulation of iron in a region of the brain known as the basal ganglia. For this reason, Kufor Rakeb syndrome is part of a group of diseases called neurodegeneration with brain iron accumulation (NBIA). People living with Kufor Rakeb syndrome also experience symptoms that don’t affect movement (non-motor symptoms), including anxiety, learning difficulties, visual and auditory hallucinations, and dementia.Treatment of Kufor Rakeb syndrome is similar to treatment of typical Parkinson’s disease and is mainly composed of a combination of two medications called levodopa (L-DOPA) and carbidopa. Other medications, such as dopamine agonists, can also be prescribed. Medication is only used to control the symptoms of the disease (symptomatic treatment), not to cure it. Benefits of medication are mostly for motor symptoms, and have no significant effect on non-motor symptoms of KRS.IntroductionKufor Rakeb syndrome was first identified in 1994 in five individuals from a large family living in a Jordanian town called Kufr Rakeb, hence the name of the disease. The gene that is altered in KRS was identified in 2006. Since that time, early detection of the disease and screening of family members is possible with genetic testing. A timely and accurate diagnosis is crucial for patients, as their symptoms can be managed with medication.
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Overview of Kufor Rakeb Syndrome. SummaryKufor Rakeb syndrome (KRS), also known as Parkinson’s disease 9, is a very rare form of inherited juvenile-onset Parkinson’s disease. Typical (idiopathic) Parkinson’s disease usually affects people aged 60 or over, but individuals affected by KRS will usually start to develop symptoms before 20 years of age. Depending on the individual, symptoms can include typical Parkinson’s disease symptoms (parkinsonism), such as slowed movements (bradykinesia), rigidity, and tremor, as well as other symptoms that are not typically associated with Parkinson’s disease, including partial or complete paralysis of the legs (paraplegia), inability to move the eyes upward (supranuclear upgaze palsy), and loss of coordination of movements (ataxia). Affected individuals also have brain atrophy (cerebral atrophy) and sometimes have an accumulation of iron in a region of the brain known as the basal ganglia. For this reason, Kufor Rakeb syndrome is part of a group of diseases called neurodegeneration with brain iron accumulation (NBIA). People living with Kufor Rakeb syndrome also experience symptoms that don’t affect movement (non-motor symptoms), including anxiety, learning difficulties, visual and auditory hallucinations, and dementia.Treatment of Kufor Rakeb syndrome is similar to treatment of typical Parkinson’s disease and is mainly composed of a combination of two medications called levodopa (L-DOPA) and carbidopa. Other medications, such as dopamine agonists, can also be prescribed. Medication is only used to control the symptoms of the disease (symptomatic treatment), not to cure it. Benefits of medication are mostly for motor symptoms, and have no significant effect on non-motor symptoms of KRS.IntroductionKufor Rakeb syndrome was first identified in 1994 in five individuals from a large family living in a Jordanian town called Kufr Rakeb, hence the name of the disease. The gene that is altered in KRS was identified in 2006. Since that time, early detection of the disease and screening of family members is possible with genetic testing. A timely and accurate diagnosis is crucial for patients, as their symptoms can be managed with medication.
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Kufor Rakeb Syndrome
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nord_687_1
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Symptoms of Kufor Rakeb Syndrome
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For most individuals, symptoms will begin to appear between 10 and 20 years of age. KRS is a neurodegenerative disorder, so the severity of symptoms tends to progress with time. Symptoms varies depending on the individual and can be divided in two major categories: symptoms that affect movement (motor symptoms) and those that do not (non-motor symptoms). Motor Symptoms
Motor symptoms can be further subdivided into typical Parkinson’s disease symptoms (parkinsonism) and symptoms that are not typically associated with Parkinson’s disease. The four main features of parkinsonism are slowed movements (bradykinesia), tremor, rigidity, and postural instability. Other symptoms present in KRS include partial or total paralysis of the legs (paraplegia), inability to move the eyes upward (supranuclear upgaze palsy), loss of coordination of movements (ataxia), muscle stiffness (spasticity), involuntary muscle contractions resulting in abnormal postures (dystonia), involuntary movements (dyskinesia), and increased reflexes (hyperreflexia). This can lead to imbalance and falls in affected individuals. A feature typical of KRS is small, involuntary muscle contractions of the fingers, face, and passage at the back of the mouth leading to the pharynx (facial-faucial-finger mini-myoclonus). Patients can also have difficulty articulating (dysarthria) or swallowing (dysphagia). Non-Motor Symptoms
Intellectual disability and learning difficulties can be the first symptoms to appear, and are among the most common non-motor symptoms. A large proportion of patients will also develop dementia. Other non-motor symptoms include severe anxiety, reduced or absent smell (hyposmia or anosmia), panic attacks, as well as visual and auditory hallucinations. Non-motor symptoms usually greatly impact the quality of life of affected individuals.
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Symptoms of Kufor Rakeb Syndrome. For most individuals, symptoms will begin to appear between 10 and 20 years of age. KRS is a neurodegenerative disorder, so the severity of symptoms tends to progress with time. Symptoms varies depending on the individual and can be divided in two major categories: symptoms that affect movement (motor symptoms) and those that do not (non-motor symptoms). Motor Symptoms
Motor symptoms can be further subdivided into typical Parkinson’s disease symptoms (parkinsonism) and symptoms that are not typically associated with Parkinson’s disease. The four main features of parkinsonism are slowed movements (bradykinesia), tremor, rigidity, and postural instability. Other symptoms present in KRS include partial or total paralysis of the legs (paraplegia), inability to move the eyes upward (supranuclear upgaze palsy), loss of coordination of movements (ataxia), muscle stiffness (spasticity), involuntary muscle contractions resulting in abnormal postures (dystonia), involuntary movements (dyskinesia), and increased reflexes (hyperreflexia). This can lead to imbalance and falls in affected individuals. A feature typical of KRS is small, involuntary muscle contractions of the fingers, face, and passage at the back of the mouth leading to the pharynx (facial-faucial-finger mini-myoclonus). Patients can also have difficulty articulating (dysarthria) or swallowing (dysphagia). Non-Motor Symptoms
Intellectual disability and learning difficulties can be the first symptoms to appear, and are among the most common non-motor symptoms. A large proportion of patients will also develop dementia. Other non-motor symptoms include severe anxiety, reduced or absent smell (hyposmia or anosmia), panic attacks, as well as visual and auditory hallucinations. Non-motor symptoms usually greatly impact the quality of life of affected individuals.
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Kufor Rakeb Syndrome
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nord_687_2
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Causes of Kufor Rakeb Syndrome
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Kufor Rakeb syndrome is an autosomal recessive disorder caused by changes (mutations) in the ATP13A2 gene. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. The ATP13A2 gene produces a protein highly expressed in the brain and neurons called ATP13A2 that is part of the ATPase protein family. The role of ATPases is to accelerate (catalyze) the decomposition (hydrolysis) of ATP (the energy currency of the cell) into ADP. This process allows energy to be utilized for other chemical reactions in the body. ATP13A2 is involved in maintaining constant levels (homeostasis) of zinc and manganese inside the cell. Mutations in the ATP13A2 gene lead to the production of a dysfunctional protein, which leads to dysregulation (dyshomeostasis) of zinc and manganese levels in the cell. This in turn leads to dysfunction in the mitochondria (responsible for energy production in the cell) and lysosomes (responsible for waste degradation in the cell), which are dependent on zinc homeostasis. Cells of patients with ATP13A2 mutations causing Kufor Rakeb syndrome therefore have impaired energy production and waste accumulation, notably of a protein called alpha-synuclein. This ultimately leads to neuronal degeneration and is thought to be responsible for the symptoms of Kufor Rakeb syndrome.Some patients also have iron accumulation in a deep brain structure called the basal ganglia (in the caudate and putamen, specifically). The mechanism by which iron accumulation occurs in the brain is not fully understood yet.
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Causes of Kufor Rakeb Syndrome. Kufor Rakeb syndrome is an autosomal recessive disorder caused by changes (mutations) in the ATP13A2 gene. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females. The ATP13A2 gene produces a protein highly expressed in the brain and neurons called ATP13A2 that is part of the ATPase protein family. The role of ATPases is to accelerate (catalyze) the decomposition (hydrolysis) of ATP (the energy currency of the cell) into ADP. This process allows energy to be utilized for other chemical reactions in the body. ATP13A2 is involved in maintaining constant levels (homeostasis) of zinc and manganese inside the cell. Mutations in the ATP13A2 gene lead to the production of a dysfunctional protein, which leads to dysregulation (dyshomeostasis) of zinc and manganese levels in the cell. This in turn leads to dysfunction in the mitochondria (responsible for energy production in the cell) and lysosomes (responsible for waste degradation in the cell), which are dependent on zinc homeostasis. Cells of patients with ATP13A2 mutations causing Kufor Rakeb syndrome therefore have impaired energy production and waste accumulation, notably of a protein called alpha-synuclein. This ultimately leads to neuronal degeneration and is thought to be responsible for the symptoms of Kufor Rakeb syndrome.Some patients also have iron accumulation in a deep brain structure called the basal ganglia (in the caudate and putamen, specifically). The mechanism by which iron accumulation occurs in the brain is not fully understood yet.
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Kufor Rakeb Syndrome
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nord_687_3
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Affects of Kufor Rakeb Syndrome
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Kufor Rakeb syndrome is considered an ultra-rare disorder. Fewer than 50 individuals have been reported in the literature. Because KRS is a rare and complex disease, it is possibly underdiagnosed and the real prevalence of the disease is therefore hard to estimate. As it is the case for all autosomal recessive disorders, children of parents who are blood relatives are at an increased risk of developing the disease, as they are more likely to receive the same copy of a disease-causing (pathogenic) mutation from each parent.
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Affects of Kufor Rakeb Syndrome. Kufor Rakeb syndrome is considered an ultra-rare disorder. Fewer than 50 individuals have been reported in the literature. Because KRS is a rare and complex disease, it is possibly underdiagnosed and the real prevalence of the disease is therefore hard to estimate. As it is the case for all autosomal recessive disorders, children of parents who are blood relatives are at an increased risk of developing the disease, as they are more likely to receive the same copy of a disease-causing (pathogenic) mutation from each parent.
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Kufor Rakeb Syndrome
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nord_687_4
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Related disorders of Kufor Rakeb Syndrome
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As Kufor Rakeb syndrome is a complex progressive neurological disease with varied symptoms, it shares features with many other disorders. The appearance of characteristic symptoms of Parkinson’s disease (parkinsonism) in individuals under age 21 is known as juvenile parkinsonism. The causes of juvenile parkinsonism are multiple, including genetic juvenile onset Parkinson’s disease (KRS being in this category), other neurological or systemic disorders, infections, toxins, and drugs side effects. The following disorders are examples of conditions that can have symptoms similar to Kufor Rakeb syndrome. Niemann-Pick disease type C (NPC) is a rare progressive genetic disorder characterized by an inability of the body to transport cholesterol and other fatty substances (lipids) inside of cells. The classic presentation of NPC occurs during middle to late childhood with clumsiness or difficulty in drawing and writing, often noted by teachers and parents. Inability to move the eye upwards (vertical supranuclear gaze palsy) may be first reported during this time from a careful neurological exam or observations by the parents. Other neurological abnormalities may be the first apparent symptoms, specifically lack of muscle coordination (cerebellar ataxia). Psychiatric disturbances and the progressive loss of memory and intellectual ability (dementia) can develop. (For more information on this disorder, choose ” Niemann-Pick disease type C ” as your search term in the Rare Disease Database.)Wilson disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, may cause liver (hepatic) disease, central nervous system dysfunction, and death. Common neurological symptoms of Wilson disease that may appear and progress with time include tremor, involuntary movements, difficulty swallowing (dysphagia), difficulty speaking and poor articulation (dysarthria), lack of coordination, dystonic postures, and muscle rigidity. (For more information on this disorder, choose ” Wilson disease ” as your search term in the Rare Disease Database.)Rapid-onset dystonia-parkinsonism (RDP), also known as DYT12, is part of a large group of movement disorders known as dystonia. It is characterized by dystonic features and additional symptoms that resemble those seen in Parkinson’s disease (parkinsonism). Classic features include involuntary dystonic muscle spasms in the arms more often than the legs and prominent involvement of speech and swallowing muscles. Parkinsonian symptoms include involuntary, rhythmic, quivering movements (tremors), slowed movements (bradykinesia), and postural instability. Seizures have been reported in some cases. (For more information on this disorder, choose ” Dystonia ” as your search term in the Rare Disease Database.)Juvenile CLN3 disease, a rare genetic disorder, belongs to a group of degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses. The symptoms of juvenile CLN3 disease usually become apparent between 5 and 15 years of age, usually with visual abnormalities that progress rapidly. Affected children also suffer from problems with their speech, cognitive decline, behavioral changes, and motor decline. Eventually, usually during the late teens or twenties, additional abnormalities develop including sudden involuntary muscle contractions (myoclonus), muscle spasms that result in slow, stiff movements of the legs, weakness or paralysis of all four limbs (quadriparesis), and sleep disturbances. (For more information on this disorder, choose ” Juvenile CLN3 disease ” as your search term in the Rare Disease Database.)Neurodegeneration with brain iron accumulation (NBIA) is a group of ten rare inherited neurodegenerative diseases that includes, among others, Kufor Rakeb syndrome, pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), and aceruloplasminemia. The common features of these disorders is that they can lead to accumulation of iron in a region of the brain called the basal ganglia, and to neurological symptoms such as muscle stiffness (spasticity), slowed movements (bradykinesia), rigidity, tremor and involuntary muscle contractions resulting in abnormal postures (dystonia). The age of onset and progression of symptoms varies depending on the disease. (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 Kufor Rakeb Syndrome. As Kufor Rakeb syndrome is a complex progressive neurological disease with varied symptoms, it shares features with many other disorders. The appearance of characteristic symptoms of Parkinson’s disease (parkinsonism) in individuals under age 21 is known as juvenile parkinsonism. The causes of juvenile parkinsonism are multiple, including genetic juvenile onset Parkinson’s disease (KRS being in this category), other neurological or systemic disorders, infections, toxins, and drugs side effects. The following disorders are examples of conditions that can have symptoms similar to Kufor Rakeb syndrome. Niemann-Pick disease type C (NPC) is a rare progressive genetic disorder characterized by an inability of the body to transport cholesterol and other fatty substances (lipids) inside of cells. The classic presentation of NPC occurs during middle to late childhood with clumsiness or difficulty in drawing and writing, often noted by teachers and parents. Inability to move the eye upwards (vertical supranuclear gaze palsy) may be first reported during this time from a careful neurological exam or observations by the parents. Other neurological abnormalities may be the first apparent symptoms, specifically lack of muscle coordination (cerebellar ataxia). Psychiatric disturbances and the progressive loss of memory and intellectual ability (dementia) can develop. (For more information on this disorder, choose ” Niemann-Pick disease type C ” as your search term in the Rare Disease Database.)Wilson disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, may cause liver (hepatic) disease, central nervous system dysfunction, and death. Common neurological symptoms of Wilson disease that may appear and progress with time include tremor, involuntary movements, difficulty swallowing (dysphagia), difficulty speaking and poor articulation (dysarthria), lack of coordination, dystonic postures, and muscle rigidity. (For more information on this disorder, choose ” Wilson disease ” as your search term in the Rare Disease Database.)Rapid-onset dystonia-parkinsonism (RDP), also known as DYT12, is part of a large group of movement disorders known as dystonia. It is characterized by dystonic features and additional symptoms that resemble those seen in Parkinson’s disease (parkinsonism). Classic features include involuntary dystonic muscle spasms in the arms more often than the legs and prominent involvement of speech and swallowing muscles. Parkinsonian symptoms include involuntary, rhythmic, quivering movements (tremors), slowed movements (bradykinesia), and postural instability. Seizures have been reported in some cases. (For more information on this disorder, choose ” Dystonia ” as your search term in the Rare Disease Database.)Juvenile CLN3 disease, a rare genetic disorder, belongs to a group of degenerative neurometabolic disorders known as the neuronal ceroid lipofuscinoses. The symptoms of juvenile CLN3 disease usually become apparent between 5 and 15 years of age, usually with visual abnormalities that progress rapidly. Affected children also suffer from problems with their speech, cognitive decline, behavioral changes, and motor decline. Eventually, usually during the late teens or twenties, additional abnormalities develop including sudden involuntary muscle contractions (myoclonus), muscle spasms that result in slow, stiff movements of the legs, weakness or paralysis of all four limbs (quadriparesis), and sleep disturbances. (For more information on this disorder, choose ” Juvenile CLN3 disease ” as your search term in the Rare Disease Database.)Neurodegeneration with brain iron accumulation (NBIA) is a group of ten rare inherited neurodegenerative diseases that includes, among others, Kufor Rakeb syndrome, pantothenate kinase-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), and aceruloplasminemia. The common features of these disorders is that they can lead to accumulation of iron in a region of the brain called the basal ganglia, and to neurological symptoms such as muscle stiffness (spasticity), slowed movements (bradykinesia), rigidity, tremor and involuntary muscle contractions resulting in abnormal postures (dystonia). The age of onset and progression of symptoms varies depending on the disease. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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Kufor Rakeb Syndrome
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Diagnosis of Kufor Rakeb Syndrome
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A diagnosis of Kufor Rakeb syndrome requires an extensive patient history, as well as a complete physical and neurological examination. KRS can be suspected in individuals that start to develop atypical parkinsonism (typical symptoms of Parkinson’s disease in addition to other features such as dystonia, muscle stiffness, and rapid progression) between 10 and 20 years of age. MRI imaging will also show brain atrophy (cerebral atrophy) and possibly accumulation of iron in a brain structure called the basal ganglia (in the caudate and putamen, specifically). Genetic screening allows the identification of disease-causing (pathogenic) changes (mutations) in the ATP13A2 gene and can lead to a definitive diagnosis.
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Diagnosis of Kufor Rakeb Syndrome. A diagnosis of Kufor Rakeb syndrome requires an extensive patient history, as well as a complete physical and neurological examination. KRS can be suspected in individuals that start to develop atypical parkinsonism (typical symptoms of Parkinson’s disease in addition to other features such as dystonia, muscle stiffness, and rapid progression) between 10 and 20 years of age. MRI imaging will also show brain atrophy (cerebral atrophy) and possibly accumulation of iron in a brain structure called the basal ganglia (in the caudate and putamen, specifically). Genetic screening allows the identification of disease-causing (pathogenic) changes (mutations) in the ATP13A2 gene and can lead to a definitive diagnosis.
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Kufor Rakeb Syndrome
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Therapies of Kufor Rakeb Syndrome
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As there is no cure for Kufor Rakeb syndrome, therapy is focused on the management of symptoms and improvement of quality of life of affected individuals. As it is the case for typical (idiopathic) Parkinson’s disease, a combination of levodopa and carbidopa is usually prescribed. The goal of this medication is to alleviate motor symptoms by increasing the concentration of dopamine in the nervous system. Dopamine receptor agonists can also be used. Trihexylphenidyl and amantadine might also be prescribed, especially in cases where dopaminergic medication is not effective or tolerated. Botulinum toxin (Botox) can be used to treat dystonia. Physical, occupational and/or speech therapy can also be useful interventions. Treatment options for non-motor symptoms are more limited.Individuals living with Kufor Rakeb syndrome might also require a walking aid or a wheelchair. Special education might be indicated, as intellectual disability and learning difficulties are common in KRS. The help of caregivers or health professionals might also be necessary to perform activities of daily living, depending on the severity of the disease. Genetic counselling services should be offered to affected families.
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Therapies of Kufor Rakeb Syndrome. As there is no cure for Kufor Rakeb syndrome, therapy is focused on the management of symptoms and improvement of quality of life of affected individuals. As it is the case for typical (idiopathic) Parkinson’s disease, a combination of levodopa and carbidopa is usually prescribed. The goal of this medication is to alleviate motor symptoms by increasing the concentration of dopamine in the nervous system. Dopamine receptor agonists can also be used. Trihexylphenidyl and amantadine might also be prescribed, especially in cases where dopaminergic medication is not effective or tolerated. Botulinum toxin (Botox) can be used to treat dystonia. Physical, occupational and/or speech therapy can also be useful interventions. Treatment options for non-motor symptoms are more limited.Individuals living with Kufor Rakeb syndrome might also require a walking aid or a wheelchair. Special education might be indicated, as intellectual disability and learning difficulties are common in KRS. The help of caregivers or health professionals might also be necessary to perform activities of daily living, depending on the severity of the disease. Genetic counselling services should be offered to affected families.
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Kufor Rakeb Syndrome
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nord_688_0
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Overview of L1 Syndrome
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SummaryL1 syndrome is an inherited, X-linked disorder occurring in males that primarily affects the nervous system. The disease is mainly characterized by hydrocephalus (increased fluid in the center of the brain), spasticity of the lower limbs (muscle stiffness), adducted thumbs (clasped towards the palm), aphasia (difficulty with speaking), seizures, and agenesis of the corpus callosum (underdeveloped or absent connecting tissue between the left and right hemispheres of the brain). Affected individuals have intellectual disability in the mild to moderate range. L1 syndrome is caused by abnormalities (mutations) in the L1CAM gene, which affects about 1 in 30,000 males.
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Overview of L1 Syndrome. SummaryL1 syndrome is an inherited, X-linked disorder occurring in males that primarily affects the nervous system. The disease is mainly characterized by hydrocephalus (increased fluid in the center of the brain), spasticity of the lower limbs (muscle stiffness), adducted thumbs (clasped towards the palm), aphasia (difficulty with speaking), seizures, and agenesis of the corpus callosum (underdeveloped or absent connecting tissue between the left and right hemispheres of the brain). Affected individuals have intellectual disability in the mild to moderate range. L1 syndrome is caused by abnormalities (mutations) in the L1CAM gene, which affects about 1 in 30,000 males.
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L1 Syndrome
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Symptoms of L1 Syndrome
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The variable types of L1 syndrome were once thought to be different diseases, but all of the following conditions are now known to be caused by mutations in the L1CAM gene:X-linked hydrocephalus with stenosis of aqueduct of Sylvius (HSAS) is characterized by severe hydrocephalus that often begins prenatally, adducted thumbs, spasticity and severe intellectual disability.MASA syndrome (mental retardation, aphasia, spastic paraplegia adducted thumbs) is characterized by mild to moderate intellectual disability, aphasia (delayed speech), hypotonia that progresses to spasticity, adducted (clasped) thumbs, and variable widening of the third ventricle in the brain.X-linked complicated hereditary spastic paraplegia type 1 is characterized by spastic paraplegia (shuffling gait), mild to moderate intellectual disability and more or less normal findings on MRI of the brain.X-linked complicated corpus callosum agenesis is characterized by variable spastic paraplegia, mild to moderate intellectual disability and abnormalities in the corpus callosum of the brain.
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Symptoms of L1 Syndrome. The variable types of L1 syndrome were once thought to be different diseases, but all of the following conditions are now known to be caused by mutations in the L1CAM gene:X-linked hydrocephalus with stenosis of aqueduct of Sylvius (HSAS) is characterized by severe hydrocephalus that often begins prenatally, adducted thumbs, spasticity and severe intellectual disability.MASA syndrome (mental retardation, aphasia, spastic paraplegia adducted thumbs) is characterized by mild to moderate intellectual disability, aphasia (delayed speech), hypotonia that progresses to spasticity, adducted (clasped) thumbs, and variable widening of the third ventricle in the brain.X-linked complicated hereditary spastic paraplegia type 1 is characterized by spastic paraplegia (shuffling gait), mild to moderate intellectual disability and more or less normal findings on MRI of the brain.X-linked complicated corpus callosum agenesis is characterized by variable spastic paraplegia, mild to moderate intellectual disability and abnormalities in the corpus callosum of the brain.
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L1 Syndrome
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nord_688_2
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Causes of L1 Syndrome
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L1 syndrome is an X-linked genetic disorder that occurs primarily in males. L1 syndrome is caused by mutations in the L1CAM gene located on the X chromosome. An abnormal gene on the X chromosome causes X-linked disorders, such as L1 syndrome. Normal females have two X chromosomes, in which one is activated chromosome and the other is inactivated. The majority of female carriers for L1 syndrome do not show symptoms because the X chromosome containing the disease gene is usually the inactivated chromosome. Males have only one X chromosome and will develop L1 syndrome if they inherit the X chromosome containing the disease gene. Affected males with X-linked disorders will always pass the gene to their daughters, but will only pass their normal Y chromosome to their sons. Therefore, all of the daughters of an affected male will be carriers for the disease while sons of an affected male will not have the disease. Sons of female carriers have a 50 percent chance of inheriting the disease while daughters have a 50 percent chance of becoming carriers.
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Causes of L1 Syndrome. L1 syndrome is an X-linked genetic disorder that occurs primarily in males. L1 syndrome is caused by mutations in the L1CAM gene located on the X chromosome. An abnormal gene on the X chromosome causes X-linked disorders, such as L1 syndrome. Normal females have two X chromosomes, in which one is activated chromosome and the other is inactivated. The majority of female carriers for L1 syndrome do not show symptoms because the X chromosome containing the disease gene is usually the inactivated chromosome. Males have only one X chromosome and will develop L1 syndrome if they inherit the X chromosome containing the disease gene. Affected males with X-linked disorders will always pass the gene to their daughters, but will only pass their normal Y chromosome to their sons. Therefore, all of the daughters of an affected male will be carriers for the disease while sons of an affected male will not have the disease. Sons of female carriers have a 50 percent chance of inheriting the disease while daughters have a 50 percent chance of becoming carriers.
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L1 Syndrome
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Affects of L1 Syndrome
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L1 syndrome is a genetic condition that occurs almost exclusively in males. The birth prevalence of the HSAS type of L1 syndrome is approximately 1 in 30,000 births. The frequency of all types of L1 syndrome is not known. Approximately 5% of female carriers of an L1CAM gene mutation have some symptoms that are usually mild.
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Affects of L1 Syndrome. L1 syndrome is a genetic condition that occurs almost exclusively in males. The birth prevalence of the HSAS type of L1 syndrome is approximately 1 in 30,000 births. The frequency of all types of L1 syndrome is not known. Approximately 5% of female carriers of an L1CAM gene mutation have some symptoms that are usually mild.
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L1 Syndrome
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Related disorders of L1 Syndrome
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In male patients with spastic paraplegia and developmental delay/intellectual disability, the L1CAM syndrome should be considered.
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Related disorders of L1 Syndrome. In male patients with spastic paraplegia and developmental delay/intellectual disability, the L1CAM syndrome should be considered.
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L1 Syndrome
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nord_688_5
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Diagnosis of L1 Syndrome
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Neuropathology and neuroimaging are used to reveal hydrocephalus with or without stenosis of the aqueduct of Sylvius, corpus callosum agenesis/hypogenesis, cerebellar hypoplasia, small brain stem, and agenesis of the pyramids.MRI or autopsy that reveals bilateral absence of the pyramids is a characteristic finding of L1 syndrome, which is a confirmed diagnosis of the disease.Molecular genetic testing for the L1CAM gene is available to confirm the diagnosis. Carrier testing for at-risk relatives, prenatal diagnosis, and preimplantation genetic diagnosis (PGD) can be performed, but requires prior information on any disease-causing mutations in the family.The diagnosis is sometimes made in a male with a nonspecific developmental delay using exome sequencing. When this is the case, a good clinical workup is needed to look for other signs of the syndrome in the affected male and in his family members. Clinical Testing and Work-Up
Patients with L1 syndrome should be closely monitored by a team of specialists and physicians. Early intervention and monitoring are very important to help the affected individual in development.
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Diagnosis of L1 Syndrome. Neuropathology and neuroimaging are used to reveal hydrocephalus with or without stenosis of the aqueduct of Sylvius, corpus callosum agenesis/hypogenesis, cerebellar hypoplasia, small brain stem, and agenesis of the pyramids.MRI or autopsy that reveals bilateral absence of the pyramids is a characteristic finding of L1 syndrome, which is a confirmed diagnosis of the disease.Molecular genetic testing for the L1CAM gene is available to confirm the diagnosis. Carrier testing for at-risk relatives, prenatal diagnosis, and preimplantation genetic diagnosis (PGD) can be performed, but requires prior information on any disease-causing mutations in the family.The diagnosis is sometimes made in a male with a nonspecific developmental delay using exome sequencing. When this is the case, a good clinical workup is needed to look for other signs of the syndrome in the affected male and in his family members. Clinical Testing and Work-Up
Patients with L1 syndrome should be closely monitored by a team of specialists and physicians. Early intervention and monitoring are very important to help the affected individual in development.
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L1 Syndrome
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Therapies of L1 Syndrome
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TreatmentThe treatment of L1 syndrome is directed toward the specific symptoms that are apparent in each individual. The best management involves the collaboration of a multidisciplinary team, which includes expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and medical genetics.Surgical treatment may need to be performed for hydrocephalus. Shunting of cerebrospinal fluid (CSF) can reduce intracranial pressure from the brain.Although surgical intervention is not usually necessary, tendon transfer may help thumb function for patients with adducted thumbs. Splints may also help reduce the severity of adduction.Intellectual disability is highly variable and developmental progress should be monitored and counseling provided.Early intervention is important to ensure that children with L1 syndrome reach their potential. Special services that may be beneficial to affected children may include special education, special social support, physical therapy, and/or other medical, social, and/or vocational services. Genetic counseling is recommended for family members of affected individuals.
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Therapies of L1 Syndrome. TreatmentThe treatment of L1 syndrome is directed toward the specific symptoms that are apparent in each individual. The best management involves the collaboration of a multidisciplinary team, which includes expertise in pediatrics, child neurology, neurosurgery, rehabilitation, and medical genetics.Surgical treatment may need to be performed for hydrocephalus. Shunting of cerebrospinal fluid (CSF) can reduce intracranial pressure from the brain.Although surgical intervention is not usually necessary, tendon transfer may help thumb function for patients with adducted thumbs. Splints may also help reduce the severity of adduction.Intellectual disability is highly variable and developmental progress should be monitored and counseling provided.Early intervention is important to ensure that children with L1 syndrome reach their potential. Special services that may be beneficial to affected children may include special education, special social support, physical therapy, and/or other medical, social, and/or vocational services. Genetic counseling is recommended for family members of affected individuals.
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L1 Syndrome
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nord_689_0
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Overview of Laband Syndrome
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Laband syndrome, also known as Zimmerman-Laband syndrome, is an extremely rare genetic disorder characterized by abnormalities of the head and facial (craniofacial) area and the hands and feet. Most children with this disorder have abnormally large gums (gingival fibromatosis). Overgrown gums may affect the ability to chew, swallow, and/or speak. In addition, affected infants may exhibit abnormally long, thin fingers and toes and/or deformed (dysplastic) or absent nails at birth. In some cases, mental retardation may also be present. In most cases, Laband syndrome is believed to be inherited as an autosomal dominant trait. However, evidence of autosomal recessive inheritance has also been reported.
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Overview of Laband Syndrome. Laband syndrome, also known as Zimmerman-Laband syndrome, is an extremely rare genetic disorder characterized by abnormalities of the head and facial (craniofacial) area and the hands and feet. Most children with this disorder have abnormally large gums (gingival fibromatosis). Overgrown gums may affect the ability to chew, swallow, and/or speak. In addition, affected infants may exhibit abnormally long, thin fingers and toes and/or deformed (dysplastic) or absent nails at birth. In some cases, mental retardation may also be present. In most cases, Laband syndrome is believed to be inherited as an autosomal dominant trait. However, evidence of autosomal recessive inheritance has also been reported.
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Laband Syndrome
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Symptoms of Laband Syndrome
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Laband syndrome is an extremely rare genetic disorder characterized by abnormalities of the head and face (craniofacial) area and the fingers and toes, particularly the thumbs and great toes. Abnormalities affecting the fingers and toes may be apparent at birth (congenital); other symptoms may not become apparent until later during childhood. The range and severity of symptoms vary from case to case. Most children with Laband syndrome develop abnormally large gums (gingival fibromatosis). Overgrowth (hypertrophy) of the gums may cause delayed eruption of teeth. Complications resulting from gingival fibromatosis may include teeth that do not meet properly (malocclusion), chewing (mastication) problems, excessive drooling (salivation), difficulty swallowing, the development of sores at the corners of the mouth, repeated gum infections, abnormal dryness of the mouth (xerostomia), premature loss (exfoliation) of teeth, and/or speech problems. In some cases, as affected children age, the gums may completely cover the teeth and protrude from the mouth. Individuals with Laband syndrome may also exhibit facial abnormalities that may become apparent during early childhood and progress throughout adolescence. These may include an abnormally narrow facial appearance and/or overgrowth of the tongue, lips, nose, and/or ears. The nose may appear rounded or large (bulbous). The cartilage of the ears and nose may also be abnormally soft. In addition, some children with this disorder may exhibit excessive hair growth (hypertrichosis). In most cases, individuals with Laband syndrome also have malformations of the hands and feet including abnormally long, slender fingers and toes (arachnodactyly) that may be large and swollen at the tips (distal phalanges). In some cases, the bones of the fingertips may be malformed and/or the joints of the fingers and hands (metacarpophalangeal joints) may be unusually flexible (hyperextensive). In addition, the nails of the hands and feet, particularly the thumbs and great toes, may be malformed (dysplastic) or absent.In some cases, individuals with Laband syndrome may exhibit other physical characteristics including additional skeletal abnormalities, spinal abnormalities, and an unusually large liver (hepatomegaly) or, less commonly, spleen (splenomegaly). Normal intelligence occurs in some cases; mental retardation ranging from mild to severe has been reported in others.
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Symptoms of Laband Syndrome. Laband syndrome is an extremely rare genetic disorder characterized by abnormalities of the head and face (craniofacial) area and the fingers and toes, particularly the thumbs and great toes. Abnormalities affecting the fingers and toes may be apparent at birth (congenital); other symptoms may not become apparent until later during childhood. The range and severity of symptoms vary from case to case. Most children with Laband syndrome develop abnormally large gums (gingival fibromatosis). Overgrowth (hypertrophy) of the gums may cause delayed eruption of teeth. Complications resulting from gingival fibromatosis may include teeth that do not meet properly (malocclusion), chewing (mastication) problems, excessive drooling (salivation), difficulty swallowing, the development of sores at the corners of the mouth, repeated gum infections, abnormal dryness of the mouth (xerostomia), premature loss (exfoliation) of teeth, and/or speech problems. In some cases, as affected children age, the gums may completely cover the teeth and protrude from the mouth. Individuals with Laband syndrome may also exhibit facial abnormalities that may become apparent during early childhood and progress throughout adolescence. These may include an abnormally narrow facial appearance and/or overgrowth of the tongue, lips, nose, and/or ears. The nose may appear rounded or large (bulbous). The cartilage of the ears and nose may also be abnormally soft. In addition, some children with this disorder may exhibit excessive hair growth (hypertrichosis). In most cases, individuals with Laband syndrome also have malformations of the hands and feet including abnormally long, slender fingers and toes (arachnodactyly) that may be large and swollen at the tips (distal phalanges). In some cases, the bones of the fingertips may be malformed and/or the joints of the fingers and hands (metacarpophalangeal joints) may be unusually flexible (hyperextensive). In addition, the nails of the hands and feet, particularly the thumbs and great toes, may be malformed (dysplastic) or absent.In some cases, individuals with Laband syndrome may exhibit other physical characteristics including additional skeletal abnormalities, spinal abnormalities, and an unusually large liver (hepatomegaly) or, less commonly, spleen (splenomegaly). Normal intelligence occurs in some cases; mental retardation ranging from mild to severe has been reported in others.
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Laband Syndrome
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nord_689_2
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Causes of Laband Syndrome
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Early reports suggest that Laband syndrome is inherited as an autosomal dominant trait. However, evidence for autosomal recessive inheritance exists as well. Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The location and nature of the genetic defect (e.g., the defective gene) responsible for Laband syndrome are not yet known. However, ongoing research studies are being conducted to help determine such information. Some researchers have indicated that a, as yet unidentified, gene on the short arm (p) of chromosome 3 may cause some cases of Laband syndrome.
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Causes of Laband Syndrome. Early reports suggest that Laband syndrome is inherited as an autosomal dominant trait. However, evidence for autosomal recessive inheritance exists as well. Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The location and nature of the genetic defect (e.g., the defective gene) responsible for Laband syndrome are not yet known. However, ongoing research studies are being conducted to help determine such information. Some researchers have indicated that a, as yet unidentified, gene on the short arm (p) of chromosome 3 may cause some cases of Laband syndrome.
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Laband Syndrome
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nord_689_3
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Affects of Laband Syndrome
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Laband syndrome is an extremely rare genetic disorder that affects males and females in equal numbers. It appears that the disease most frequently affects individuals who are of Eastern Indian ancestry from India and the West Indies. However, the disorder has also been reported in individuals of European descent. More than 30 cases have been reported in the medical literature since the disorder's original description in 1928. Abnormalities affecting the fingers and toes may be apparent at birth (congenital); however, other symptoms may not become apparent until childhood. Gingival fibromatosis may not occur until a child's primary (deciduous) teeth begin to appear.
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Affects of Laband Syndrome. Laband syndrome is an extremely rare genetic disorder that affects males and females in equal numbers. It appears that the disease most frequently affects individuals who are of Eastern Indian ancestry from India and the West Indies. However, the disorder has also been reported in individuals of European descent. More than 30 cases have been reported in the medical literature since the disorder's original description in 1928. Abnormalities affecting the fingers and toes may be apparent at birth (congenital); however, other symptoms may not become apparent until childhood. Gingival fibromatosis may not occur until a child's primary (deciduous) teeth begin to appear.
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Laband Syndrome
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nord_689_4
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Related disorders of Laband Syndrome
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Symptoms of the following disorder can be similar to those of Laband syndrome. Comparisons may be useful for a differential diagnosis: Gingival fibromatosis with hypertrichosis is an extremely rare disorder characterized by abnormally large gums (gingival fibromatosis) and excessive hair growth (hypertrichosis). Gingival fibromatosis usually occurs when an affected child's primary (deciduous) teeth erupt from the gums. Complications resulting from gingival fibromatosis may include teeth that do not meet properly (malocclusion), chewing (mastication) problems, excessive drooling (salivation), difficulty swallowing, the development of sores at the corners of the mouth, repeated gum infections, and/or speech problems. Other physical characteristics may include abnormal dryness of the mouth (xerostomia), failure of the teeth to erupt, and/or loss of teeth (exfoliation). Affected individuals may also exhibit mental retardation and/or diminished muscle tone (hypotonia). Approximately half of affected individuals may also exhibit seizure activity (epilepsy) and/or impaired intellectual function (oligophrenia). Gingival fibromatosis with hypertrichosis is thought to be inherited as an autosomal dominant trait. Juvenile hyaline fibromatosis, also known as Murray-Puretic-Drescher syndrome, is an extremely rare genetic disorder characterized by overgrowth of the gums (gingival fibromatosis), large joints that are stuck in a bent position and cannot be straightened (flexion contractures), and small growths (papules or nodules) on the scalp, hands, ears, and near the nose. Affected individuals may also develop skin tumors, degeneration of bone tissue (osteolysis) and loss of bone mass that makes individuals prone to fractures (osteoporosis). Affected individuals also experience the buildup of hyaline, a collagen-like substance, within the body. Juvenile hyaline fibromatosis is inherited as an autosomal recessive trait.Individuals who exhibit abnormally large gums (gingival fibromatosis) and excessive hair growth (hypertrichosis) have had epilepsy and mental retardation. Epilepsy is a group of disorders of the central nervous system characterized by repeated (paroxysmal) convulsive electrical disturbances in the brain. The major symptoms may include convulsions, spasms, sensory confusion, disturbances in the nerves that control involuntary body functions (autonomic nervous system), and/or loss of consciousness (syncope). In some instances, gingival hypertrophy may be secondary to anticonvulsant drugs that may be used to treat epilepsy. (For more information on this disorder, choose “Epilepsy” as your search term in the Rare Disease Database.)
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Related disorders of Laband Syndrome. Symptoms of the following disorder can be similar to those of Laband syndrome. Comparisons may be useful for a differential diagnosis: Gingival fibromatosis with hypertrichosis is an extremely rare disorder characterized by abnormally large gums (gingival fibromatosis) and excessive hair growth (hypertrichosis). Gingival fibromatosis usually occurs when an affected child's primary (deciduous) teeth erupt from the gums. Complications resulting from gingival fibromatosis may include teeth that do not meet properly (malocclusion), chewing (mastication) problems, excessive drooling (salivation), difficulty swallowing, the development of sores at the corners of the mouth, repeated gum infections, and/or speech problems. Other physical characteristics may include abnormal dryness of the mouth (xerostomia), failure of the teeth to erupt, and/or loss of teeth (exfoliation). Affected individuals may also exhibit mental retardation and/or diminished muscle tone (hypotonia). Approximately half of affected individuals may also exhibit seizure activity (epilepsy) and/or impaired intellectual function (oligophrenia). Gingival fibromatosis with hypertrichosis is thought to be inherited as an autosomal dominant trait. Juvenile hyaline fibromatosis, also known as Murray-Puretic-Drescher syndrome, is an extremely rare genetic disorder characterized by overgrowth of the gums (gingival fibromatosis), large joints that are stuck in a bent position and cannot be straightened (flexion contractures), and small growths (papules or nodules) on the scalp, hands, ears, and near the nose. Affected individuals may also develop skin tumors, degeneration of bone tissue (osteolysis) and loss of bone mass that makes individuals prone to fractures (osteoporosis). Affected individuals also experience the buildup of hyaline, a collagen-like substance, within the body. Juvenile hyaline fibromatosis is inherited as an autosomal recessive trait.Individuals who exhibit abnormally large gums (gingival fibromatosis) and excessive hair growth (hypertrichosis) have had epilepsy and mental retardation. Epilepsy is a group of disorders of the central nervous system characterized by repeated (paroxysmal) convulsive electrical disturbances in the brain. The major symptoms may include convulsions, spasms, sensory confusion, disturbances in the nerves that control involuntary body functions (autonomic nervous system), and/or loss of consciousness (syncope). In some instances, gingival hypertrophy may be secondary to anticonvulsant drugs that may be used to treat epilepsy. (For more information on this disorder, choose “Epilepsy” as your search term in the Rare Disease Database.)
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Laband Syndrome
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Diagnosis of Laband Syndrome
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In most cases, Laband syndrome may be diagnosed during early childhood. The diagnosis may be confirmed based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. X-ray studies of the fingers and/or toes (digits) and clinical examination of the nose, ears, lips, and tongue may be helpful in identifying the disorder. Malformation or absence of the nails may be apparent at birth (congenital). Confirmation of Laband syndrome may not be made until gingival fibromatosis is observed when the primary teeth appear.
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Diagnosis of Laband Syndrome. In most cases, Laband syndrome may be diagnosed during early childhood. The diagnosis may be confirmed based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. X-ray studies of the fingers and/or toes (digits) and clinical examination of the nose, ears, lips, and tongue may be helpful in identifying the disorder. Malformation or absence of the nails may be apparent at birth (congenital). Confirmation of Laband syndrome may not be made until gingival fibromatosis is observed when the primary teeth appear.
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Laband Syndrome
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Therapies of Laband Syndrome
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TreatmentThe treatment of Laband syndrome is directed toward the specific symptoms that are apparent in each affected individual. Pediatricians; specialists who assess and correct irregularities of the teeth (dentists and orthodontists); specialists who diagnose and treat skeletal abnormalities (orthopedists); orthopedic and dental surgeons; specialists who treat disorders affecting the tissues supporting and surrounding the teeth (periodontists); and/or other health care professionals may need to work together to ensure a comprehensive, systematic approach to treatment.Specific therapies for the treatment of Laband syndrome are symptomatic and supportive. In some cases, proper oral hygiene may postpone the appearance of abnormalities in the gums and may reduce their severity. Gum abnormalities may also be treated by surgical means (excision). Despite these efforts, overgrowth of the gums may recur. In cases where the gums cover the teeth, maintaining oral hygiene may be difficult.Because affected children may be at risk for abnormal enlargement of the liver or spleen, prompt diagnosis of Laband syndrome is critical to ensure appropriate early treatment.Individuals with gingival fibromatosis and hypertrichosis may be at an increased risk for convulsive seizures (epilepsy). Epilepsy may be treated with anticonvulsant drugs that may help to control or prevent seizure activity.Early intervention is important in ensuring that children with Laband syndrome reach their potential. Special services that may be beneficial may include remedial education, physical therapy, speech therapy, and other medical, social, and/or vocational services.Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Laband Syndrome. TreatmentThe treatment of Laband syndrome is directed toward the specific symptoms that are apparent in each affected individual. Pediatricians; specialists who assess and correct irregularities of the teeth (dentists and orthodontists); specialists who diagnose and treat skeletal abnormalities (orthopedists); orthopedic and dental surgeons; specialists who treat disorders affecting the tissues supporting and surrounding the teeth (periodontists); and/or other health care professionals may need to work together to ensure a comprehensive, systematic approach to treatment.Specific therapies for the treatment of Laband syndrome are symptomatic and supportive. In some cases, proper oral hygiene may postpone the appearance of abnormalities in the gums and may reduce their severity. Gum abnormalities may also be treated by surgical means (excision). Despite these efforts, overgrowth of the gums may recur. In cases where the gums cover the teeth, maintaining oral hygiene may be difficult.Because affected children may be at risk for abnormal enlargement of the liver or spleen, prompt diagnosis of Laband syndrome is critical to ensure appropriate early treatment.Individuals with gingival fibromatosis and hypertrichosis may be at an increased risk for convulsive seizures (epilepsy). Epilepsy may be treated with anticonvulsant drugs that may help to control or prevent seizure activity.Early intervention is important in ensuring that children with Laband syndrome reach their potential. Special services that may be beneficial may include remedial education, physical therapy, speech therapy, and other medical, social, and/or vocational services.Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Laband Syndrome
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Overview of LADD syndrome
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Lacrimo-auriculo-dento-digital (LADD) syndrome is an extremely rare genetic disorder characterized by abnormalities affecting the lacrimal and salivary glands and ducts, ears, teeth and fingers and toes. The most common findings involve malformations in the network of structures of the eye that secrete tears and drain them from the eyes (lacrimal apparatus) and abnormalities of the forearms and fingers. Specific symptoms may vary greatly from person to person. LADD syndrome may occur sporadically or be inherited in an autosomal dominant pattern.
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Overview of LADD syndrome. Lacrimo-auriculo-dento-digital (LADD) syndrome is an extremely rare genetic disorder characterized by abnormalities affecting the lacrimal and salivary glands and ducts, ears, teeth and fingers and toes. The most common findings involve malformations in the network of structures of the eye that secrete tears and drain them from the eyes (lacrimal apparatus) and abnormalities of the forearms and fingers. Specific symptoms may vary greatly from person to person. LADD syndrome may occur sporadically or be inherited in an autosomal dominant pattern.
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LADD syndrome
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Symptoms of LADD syndrome
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The symptoms of LADD syndrome may greatly vary from person to person. Abnormalities may potentially affect multiple organ systems of the body including the eyes, ears, teeth, and limbs.Malformations in the network of structures of the eye that secrete tears and drain them from the eyes are often found with LADD syndrome. These malformations may include an underdeveloped (hypoplastic) or missing (aplastic) opening in the edge of each eyelid that is linked to the tear duct (lacrimal puncta) and/or an obstruction of the channel that carries tears from the tear sac to the nasal opening (nasolacrimal duct). Absence of the lacrimal puncta is associated with excessive tearing (epiphora), inflammation of the tear sac (dacryocystitis), and keratoconjuntivitis, a condition marked by dryness and inflammation of the cornea and the membrane lining the eyes (conjunctiva). In some people, underdevelopment or absence of the tear sacs may occur resulting in an absence of tears (alacrima) and dry eyes (xerophthalmia). Less often, an abnormal passage (fistula) from the tear sac to the nasal opening may develop.Underdevelopment or absence of the salivary glands including the parotid and submandibular glands may occur. The parotid glands are located in front and below the ears and secrete saliva into the mouth. The submandibular glands are located underneath the tongue and also secrete saliva into the mouth. Salivary gland abnormalities may result in dry mouth (xerostomia) and a susceptibility to severe tooth cavities (caries). Affected individuals may also have small, underdeveloped (hypoplastic) teeth with thin enamel, peg-shaped incisors, and delayed eruption of primary teeth.Individuals with LADD syndrome may have cup-shaped, low-set ears. Hearing loss, which has ranged from mild to severe, has also been reported. Hearing loss may due to blockage of sound waves (conductive), nerve impairment (sensorineural) or both (mixed).Abnormalities affecting the forearms and hands occur in most individuals with LADD syndrome. The tip of the thumb may be clefted or split in two (bifid thumb) and three bones (phalanges) may be found in the thumb instead of two (triphalangeal thumb). In some affected individuals, the thumb may be underdeveloped or absent. Additional abnormalities may occur including shortening of the forearm bones (radius and ulna), webbing of the index and middle fingers, and abnormal curving of the pinky toward the ring finger (clinodactyly). In some people, toe abnormalities have also been reported.Additional findings have been reported in some individuals with LADD syndrome including widely-spaced eyes (hypertelorism), abnormally increased distance between the inner corners of the eyes (telecanthus), downward slanting eyelid folds (palpebral fissures), and a broad forehead. Split-hand deformity has been reported in some people. Abnormalities of genitourinary system may also occur including the abnormal location of the urethral opening on the underside of the penis (hypospadias), hardening of the kidneys (neprhosclerosis), abnormal accumulation of urine in the kidneys (hydronephrosis) or absence (agenesis) of a kidney.
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Symptoms of LADD syndrome. The symptoms of LADD syndrome may greatly vary from person to person. Abnormalities may potentially affect multiple organ systems of the body including the eyes, ears, teeth, and limbs.Malformations in the network of structures of the eye that secrete tears and drain them from the eyes are often found with LADD syndrome. These malformations may include an underdeveloped (hypoplastic) or missing (aplastic) opening in the edge of each eyelid that is linked to the tear duct (lacrimal puncta) and/or an obstruction of the channel that carries tears from the tear sac to the nasal opening (nasolacrimal duct). Absence of the lacrimal puncta is associated with excessive tearing (epiphora), inflammation of the tear sac (dacryocystitis), and keratoconjuntivitis, a condition marked by dryness and inflammation of the cornea and the membrane lining the eyes (conjunctiva). In some people, underdevelopment or absence of the tear sacs may occur resulting in an absence of tears (alacrima) and dry eyes (xerophthalmia). Less often, an abnormal passage (fistula) from the tear sac to the nasal opening may develop.Underdevelopment or absence of the salivary glands including the parotid and submandibular glands may occur. The parotid glands are located in front and below the ears and secrete saliva into the mouth. The submandibular glands are located underneath the tongue and also secrete saliva into the mouth. Salivary gland abnormalities may result in dry mouth (xerostomia) and a susceptibility to severe tooth cavities (caries). Affected individuals may also have small, underdeveloped (hypoplastic) teeth with thin enamel, peg-shaped incisors, and delayed eruption of primary teeth.Individuals with LADD syndrome may have cup-shaped, low-set ears. Hearing loss, which has ranged from mild to severe, has also been reported. Hearing loss may due to blockage of sound waves (conductive), nerve impairment (sensorineural) or both (mixed).Abnormalities affecting the forearms and hands occur in most individuals with LADD syndrome. The tip of the thumb may be clefted or split in two (bifid thumb) and three bones (phalanges) may be found in the thumb instead of two (triphalangeal thumb). In some affected individuals, the thumb may be underdeveloped or absent. Additional abnormalities may occur including shortening of the forearm bones (radius and ulna), webbing of the index and middle fingers, and abnormal curving of the pinky toward the ring finger (clinodactyly). In some people, toe abnormalities have also been reported.Additional findings have been reported in some individuals with LADD syndrome including widely-spaced eyes (hypertelorism), abnormally increased distance between the inner corners of the eyes (telecanthus), downward slanting eyelid folds (palpebral fissures), and a broad forehead. Split-hand deformity has been reported in some people. Abnormalities of genitourinary system may also occur including the abnormal location of the urethral opening on the underside of the penis (hypospadias), hardening of the kidneys (neprhosclerosis), abnormal accumulation of urine in the kidneys (hydronephrosis) or absence (agenesis) of a kidney.
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LADD syndrome
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Causes of LADD syndrome
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LADD syndrome may occur randomly as the result of a spontaneous genetic change (i.e., new mutation). The mutation is inherited in an autosomal dominant fashion. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.Investigators have determined that LADD syndrome occurs due to disruption or changes (mutations) in one of at least three genes-the fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3) gene located on chromosome 4 (4p13) and fibroblast growth factor 10 (FGF10) gene located on chromosome 5 (5p13-p12). 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 5p13-p12” refers to bands 13-12 on the short arm of chromosome 5. The numbered bands specify the location on each chromosome.
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Causes of LADD syndrome. LADD syndrome may occur randomly as the result of a spontaneous genetic change (i.e., new mutation). The mutation is inherited in an autosomal dominant fashion. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.Investigators have determined that LADD syndrome occurs due to disruption or changes (mutations) in one of at least three genes-the fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3) gene located on chromosome 4 (4p13) and fibroblast growth factor 10 (FGF10) gene located on chromosome 5 (5p13-p12). 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 5p13-p12” refers to bands 13-12 on the short arm of chromosome 5. The numbered bands specify the location on each chromosome.
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LADD syndrome
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Affects of LADD syndrome
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LADD syndrome affects males and females in equal numbers. More than 50 cases have been reported in the medical literature since the disorders first description in 1967.
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Affects of LADD syndrome. LADD syndrome affects males and females in equal numbers. More than 50 cases have been reported in the medical literature since the disorders first description in 1967.
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LADD syndrome
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Related disorders of LADD syndrome
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Symptoms of the following disorders can be similar to those of LADD syndrome. Comparisons may be useful for a differential diagnosis.Aplasia of the lacrimal and salivary glands (ALSG) is a rare genetic disorder characterized by absence (aplasia) or underdevelopment (hypoplasia) of the glands that secrete tears (lacrimal glands) and secrete saliva (salivary glands). Affected individuals may develop dry eyes (xerophthalmia) or dry mouth (xerostomia). These conditions may cause affected individuals to develop scarring of the membrane lining the eye (conjunctiva), dental erosion, gum (periodontal) disease and may make individuals extremely susceptible to developing cavities (dental caries). Inflammation of the tear sac (dacryocystitis) may also occur. Researchers have found that ALSG and (some cases of) LADD syndrome are allelic disorders meaning that they are caused by different mutations of the same gene (FGF10). ALSG is inherited as an autosomal dominant disorder.EEC syndrome, also known as ectrodactyly-ectodermal dysplasia-cleft lip/palate, is a rare genetic disorder that may be characterized by absence of all or a portion of one or more fingers and/or toes (ectrodactyly) or other digital malformations; incomplete closure of the roof of the mouth (cleft palate) and an abnormal groove in the upper lip (cleft lip); and/or other characteristic abnormalities. Additional symptoms and findings often include fine, sparse, abnormally light (hypopigmented) scalp hair and eyebrows; absent eyelashes; and/or abnormalities of the tear (lacrimal) ducts that may cause abnormal tearing, increased susceptibility to eye infections, and chronic inflammation of the delicate membranes that line the inside of the eyelids (conjunctivitis), potentially causing visual impairment. Affected individuals may also exhibit irregularities of the nails (nail dysplasia); absence and/or abnormal smallness of certain teeth (hypodontia and/or microdontia); a decreased number of hair follicles and/or sebaceous glands; and, in some cases, skin abnormalities including unusual dryness of the skin and scaling, itchy (pruritic) skin rashes. In many patients, additional symptoms and findings may be associated with EEC syndrome including absence of the mucous membrane normally lining the voice box (larynx), causing abnormal tone of the voice; abnormalities of the urinary tract; deafness; and/or other abnormalities. The range and severity of symptoms and physical findings associated with the disorder vary widely from case to case. EEC syndrome is inherited as an autosomal dominant disorder and mostly occurs due to new mutations. (For more information on this disorder, choose “ectrodactyly ectodermal” as your search term in the Rare Disease Database.)
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Related disorders of LADD syndrome. Symptoms of the following disorders can be similar to those of LADD syndrome. Comparisons may be useful for a differential diagnosis.Aplasia of the lacrimal and salivary glands (ALSG) is a rare genetic disorder characterized by absence (aplasia) or underdevelopment (hypoplasia) of the glands that secrete tears (lacrimal glands) and secrete saliva (salivary glands). Affected individuals may develop dry eyes (xerophthalmia) or dry mouth (xerostomia). These conditions may cause affected individuals to develop scarring of the membrane lining the eye (conjunctiva), dental erosion, gum (periodontal) disease and may make individuals extremely susceptible to developing cavities (dental caries). Inflammation of the tear sac (dacryocystitis) may also occur. Researchers have found that ALSG and (some cases of) LADD syndrome are allelic disorders meaning that they are caused by different mutations of the same gene (FGF10). ALSG is inherited as an autosomal dominant disorder.EEC syndrome, also known as ectrodactyly-ectodermal dysplasia-cleft lip/palate, is a rare genetic disorder that may be characterized by absence of all or a portion of one or more fingers and/or toes (ectrodactyly) or other digital malformations; incomplete closure of the roof of the mouth (cleft palate) and an abnormal groove in the upper lip (cleft lip); and/or other characteristic abnormalities. Additional symptoms and findings often include fine, sparse, abnormally light (hypopigmented) scalp hair and eyebrows; absent eyelashes; and/or abnormalities of the tear (lacrimal) ducts that may cause abnormal tearing, increased susceptibility to eye infections, and chronic inflammation of the delicate membranes that line the inside of the eyelids (conjunctivitis), potentially causing visual impairment. Affected individuals may also exhibit irregularities of the nails (nail dysplasia); absence and/or abnormal smallness of certain teeth (hypodontia and/or microdontia); a decreased number of hair follicles and/or sebaceous glands; and, in some cases, skin abnormalities including unusual dryness of the skin and scaling, itchy (pruritic) skin rashes. In many patients, additional symptoms and findings may be associated with EEC syndrome including absence of the mucous membrane normally lining the voice box (larynx), causing abnormal tone of the voice; abnormalities of the urinary tract; deafness; and/or other abnormalities. The range and severity of symptoms and physical findings associated with the disorder vary widely from case to case. EEC syndrome is inherited as an autosomal dominant disorder and mostly occurs due to new mutations. (For more information on this disorder, choose “ectrodactyly ectodermal” as your search term in the Rare Disease Database.)
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LADD syndrome
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Diagnosis of LADD syndrome
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Molecular genetic testing of the FGF10 gene and selected regions of the FGRF2/3 genes is available to confirm the diagnosis. For information contact:Jeff Milunsky, M.D.
Co- Director, Center for Human Genetics
Director, Clinical Genetics; Senior Director, Molecular Genetics
Cambridge, MA USA
http://www.chginc.org/
[email protected]
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Diagnosis of LADD syndrome. Molecular genetic testing of the FGF10 gene and selected regions of the FGRF2/3 genes is available to confirm the diagnosis. For information contact:Jeff Milunsky, M.D.
Co- Director, Center for Human Genetics
Director, Clinical Genetics; Senior Director, Molecular Genetics
Cambridge, MA USA
http://www.chginc.org/
[email protected]
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LADD syndrome
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Therapies of LADD syndrome
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Treatment
The treatment of LADD syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dental specialists, specialists who assess and treat hearing problems (audiologists), eye specialists and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Specific treatment options may include surgery, when appropriate, to relieve the discomfort causing by malfunctioning parts of the lacrimal apparatus or to correct abnormalities of the fingers, toes and forearms. Hearing aids may benefit some individuals with hearing loss. Dental care is required on a regular basis. Artificial tear substitutes may be used to treat dry eyes.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of LADD syndrome. Treatment
The treatment of LADD syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, dental specialists, specialists who assess and treat hearing problems (audiologists), eye specialists and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Specific treatment options may include surgery, when appropriate, to relieve the discomfort causing by malfunctioning parts of the lacrimal apparatus or to correct abnormalities of the fingers, toes and forearms. Hearing aids may benefit some individuals with hearing loss. Dental care is required on a regular basis. Artificial tear substitutes may be used to treat dry eyes.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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LADD syndrome
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Overview of Lafora Disease
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Summary
Lafora disease is a rare neurological condition. Early symptoms include neurological issues beginning during adolescence from 8-19 years of age. These issues can include trouble in school, frequent headaches and seizures. Lafora disease occurs when the body does not properly process glycogen, which is a source of stored energy. When glycogen is not processed properly, it builds up in the body and forms clumps called “Lafora bodies” that interfere with proper function of the brain and other physical systems.Lafora disease is an autosomal recessive genetic condition caused by changes (pathogenic variants or mutations) in the genes EPM2A or EPM2B (also called NHLRC1).Introduction
Progressive myoclonic epilepsies are a group of rare neurological conditions characterized by myoclonus, generalized epilepsy and neurological decline or neurodegeneration. Myoclonus is a rapid movement of a muscle or group of muscles that appears like a twitch or jerk. Some forms of myoclonus have brain electrical changes on testing called an electroencephalogram (EEG) that makes them similar to a brief seizure. Lafora disease is classified as a progressive myoclonic epilepsy condition. Lafora disease was first described in 1911 by Gonzalo Lafora.
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Overview of Lafora Disease. Summary
Lafora disease is a rare neurological condition. Early symptoms include neurological issues beginning during adolescence from 8-19 years of age. These issues can include trouble in school, frequent headaches and seizures. Lafora disease occurs when the body does not properly process glycogen, which is a source of stored energy. When glycogen is not processed properly, it builds up in the body and forms clumps called “Lafora bodies” that interfere with proper function of the brain and other physical systems.Lafora disease is an autosomal recessive genetic condition caused by changes (pathogenic variants or mutations) in the genes EPM2A or EPM2B (also called NHLRC1).Introduction
Progressive myoclonic epilepsies are a group of rare neurological conditions characterized by myoclonus, generalized epilepsy and neurological decline or neurodegeneration. Myoclonus is a rapid movement of a muscle or group of muscles that appears like a twitch or jerk. Some forms of myoclonus have brain electrical changes on testing called an electroencephalogram (EEG) that makes them similar to a brief seizure. Lafora disease is classified as a progressive myoclonic epilepsy condition. Lafora disease was first described in 1911 by Gonzalo Lafora.
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Lafora Disease
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Symptoms of Lafora Disease
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Lafora disease is characterized by an onset of symptoms between 8-19 years of age, with the peak symptom onset being between 14-16 years. There are also extremely rare cases of early onset Lafora disease in patients as young as 5 years. Most affected individuals do not have symptoms until adolescence and then may start to have headaches, trouble learning in school and, most characteristically, seizures. The most common type of seizure in Lafora disease is myoclonic seizures, which look like jerking or brief shaking movements. Other seizure types include tonic-clonic seizures (stiffening of muscles followed by jerking or shaking), absence seizures (“staring spells”), atonic seizures (the body becomes limp), and complex partial seizures (“staring spells” with jerking or repetitive movements in one part of the body). Focal occipital seizures that present as blindness or hallucinations are possible. Over time, seizures typically increase in severity and become more difficult to control. Status epilepticus (prolonged or back-to-back seizures) may occur. Motor and movement symptoms can include difficulty with balance, walking, coordination and spasticity. Cognitive and psychiatric features can include difficulty speaking, behavioral changes, depression, apathy and progressive dementia. Progression of Lafora disease leads to intractable myoclonus, loss of physical functions and severe cognitive decline. Within 6 years of disease onset, around half of individuals affected by Lafora disease will lose the ability to voluntarily move their body and/or cognitively interact with their surroundings. Despite this, 50% of affected individuals survive more than 11 years after presentation of first symptoms. Some affected children have shown a later onset, slower progression of symptoms and live longer than what is typical for most patients with Lafora disease.
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Symptoms of Lafora Disease. Lafora disease is characterized by an onset of symptoms between 8-19 years of age, with the peak symptom onset being between 14-16 years. There are also extremely rare cases of early onset Lafora disease in patients as young as 5 years. Most affected individuals do not have symptoms until adolescence and then may start to have headaches, trouble learning in school and, most characteristically, seizures. The most common type of seizure in Lafora disease is myoclonic seizures, which look like jerking or brief shaking movements. Other seizure types include tonic-clonic seizures (stiffening of muscles followed by jerking or shaking), absence seizures (“staring spells”), atonic seizures (the body becomes limp), and complex partial seizures (“staring spells” with jerking or repetitive movements in one part of the body). Focal occipital seizures that present as blindness or hallucinations are possible. Over time, seizures typically increase in severity and become more difficult to control. Status epilepticus (prolonged or back-to-back seizures) may occur. Motor and movement symptoms can include difficulty with balance, walking, coordination and spasticity. Cognitive and psychiatric features can include difficulty speaking, behavioral changes, depression, apathy and progressive dementia. Progression of Lafora disease leads to intractable myoclonus, loss of physical functions and severe cognitive decline. Within 6 years of disease onset, around half of individuals affected by Lafora disease will lose the ability to voluntarily move their body and/or cognitively interact with their surroundings. Despite this, 50% of affected individuals survive more than 11 years after presentation of first symptoms. Some affected children have shown a later onset, slower progression of symptoms and live longer than what is typical for most patients with Lafora disease.
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Lafora Disease
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Causes of Lafora Disease
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Lafora disease is caused by changes (pathogenic variants or mutations) in the EPM2A or EPM2B (also called NHLRC1) genes. EPM2A encodes the protein laforin, which is a phosphatase that forms a complex with the ubiquitin ligase, malin, encoded by EPM2B. The malin-laforin complex aids in monitoring and preventing excessive elongation of glycogen branch chains. When elongation is uncontrolled, glycogen branch chains cause glycogen molecules to precipitate into “Lafora bodies,” or abnormal glycogen particles which cannot be broken down and instead form accumulations that damage cells. These Lafora bodies build up throughout the nervous system as well as in tissues such as muscle, liver and skin. Lafora disease occurs when harmful variants in the EPM2A or EPM2B gene cause improper glycogen regulation by the malin-laforin complex. Over time, the buildup of Lafora bodies interferes with nervous system functioning, resulting in seizures, motor and cognitive decline characteristic of Lafora disease. More research is needed to help understand how different harmful variants in the EPM2A and EPM2B genes specifically impact glycogen processing regulation.Lafora disease is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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Causes of Lafora Disease. Lafora disease is caused by changes (pathogenic variants or mutations) in the EPM2A or EPM2B (also called NHLRC1) genes. EPM2A encodes the protein laforin, which is a phosphatase that forms a complex with the ubiquitin ligase, malin, encoded by EPM2B. The malin-laforin complex aids in monitoring and preventing excessive elongation of glycogen branch chains. When elongation is uncontrolled, glycogen branch chains cause glycogen molecules to precipitate into “Lafora bodies,” or abnormal glycogen particles which cannot be broken down and instead form accumulations that damage cells. These Lafora bodies build up throughout the nervous system as well as in tissues such as muscle, liver and skin. Lafora disease occurs when harmful variants in the EPM2A or EPM2B gene cause improper glycogen regulation by the malin-laforin complex. Over time, the buildup of Lafora bodies interferes with nervous system functioning, resulting in seizures, motor and cognitive decline characteristic of Lafora disease. More research is needed to help understand how different harmful variants in the EPM2A and EPM2B genes specifically impact glycogen processing regulation.Lafora disease is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
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Affects of Lafora Disease
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Lafora disease typically affects adolescent females and males equally and has been reported at higher frequencies in populations from the Mediterranean (Spain, France, Italy), Northern Africa, India and Pakistan. The disease prevalence from reported cases is around 4 per 1,000,000 people; however, this number may be an underestimate due to unreported or undiagnosed cases.
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Affects of Lafora Disease. Lafora disease typically affects adolescent females and males equally and has been reported at higher frequencies in populations from the Mediterranean (Spain, France, Italy), Northern Africa, India and Pakistan. The disease prevalence from reported cases is around 4 per 1,000,000 people; however, this number may be an underestimate due to unreported or undiagnosed cases.
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Related disorders of Lafora Disease
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There are many conditions with symptoms that are similar to Lafora disease. They include, but are not limited to:Juvenile myoclonic epilepsy (JME), in the past referred to as Janz syndrome, is an epilepsy syndrome characterized by myoclonic jerks and generalized tonic-clonic seizures. This condition has a similar presentation and age of onset to Lafora disease but there is no progression of epilepsy, patients do not have EEG background slowing and there is no cognitive or motor deterioration. The genetic cause of JME is only rarely identified and is an area of ongoing research; there are likely many genes or gene-gene interactions involved. Unverricht-Lundborg disease, also referred to as progressive myoclonic epilepsy type 1 or EPM1, is characterized by stimulus-sensitive myoclonus and tonic-clonic seizures. Signs and symptoms begin during childhood or adolescence and worsen over time. People with EPM1 develop ataxia (lack of coordination and balance), intention tremor, dysarthria, emotional sensitivity, depression and cognitive decline. However, EPM1 differs from Lafora in that the age of onset is earlier, EPM1 has a slower rate of disease progression and there are no Lafora bodies on skin biopsy. EPM1 is caused by pathogenic variants in the CSTB gene and is inherited in an autosomal recessive pattern. Myoclonic epilepsy with ragged red fibers (MERRF) is an extremely rare multisystem mitochondrial disorder that affects the nervous system, skeletal muscles and other organs that can present at any age after normal development earlier in life. Its distinguishing features are myoclonus, generalized epilepsy, ataxia, myopathy and dementia. Short stature, optic atrophy, hearing loss, cardiomyopathy and peripheral neuropathy are all also common symptoms in individuals with MERRF. It can be ruled out in Lafora patients by examining cerebrospinal fluid concentrations or imaging spectroscopy for lactate. Pathogenic variants in mitochondrial genes cause MERRF. (For more information, choose “MERRF Syndrome” as your search term in the Rare Disease Database.)Subacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder characterized by encephalitis that develops as a result of measles infection. The initial infection typically occurs early in childhood and then lies dormant for 6-8 years before neurological symptoms begin. These symptoms can include cognitive decline, behavioral changes, myoclonic jerks, seizures and vision issues. SSPE can be ruled out in Lafora patients by examining measles antibody titers. (For more information, choose “Subacute Sclerosing Panencephalitis” as your search term in the Rare Disease Database.)
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Related disorders of Lafora Disease. There are many conditions with symptoms that are similar to Lafora disease. They include, but are not limited to:Juvenile myoclonic epilepsy (JME), in the past referred to as Janz syndrome, is an epilepsy syndrome characterized by myoclonic jerks and generalized tonic-clonic seizures. This condition has a similar presentation and age of onset to Lafora disease but there is no progression of epilepsy, patients do not have EEG background slowing and there is no cognitive or motor deterioration. The genetic cause of JME is only rarely identified and is an area of ongoing research; there are likely many genes or gene-gene interactions involved. Unverricht-Lundborg disease, also referred to as progressive myoclonic epilepsy type 1 or EPM1, is characterized by stimulus-sensitive myoclonus and tonic-clonic seizures. Signs and symptoms begin during childhood or adolescence and worsen over time. People with EPM1 develop ataxia (lack of coordination and balance), intention tremor, dysarthria, emotional sensitivity, depression and cognitive decline. However, EPM1 differs from Lafora in that the age of onset is earlier, EPM1 has a slower rate of disease progression and there are no Lafora bodies on skin biopsy. EPM1 is caused by pathogenic variants in the CSTB gene and is inherited in an autosomal recessive pattern. Myoclonic epilepsy with ragged red fibers (MERRF) is an extremely rare multisystem mitochondrial disorder that affects the nervous system, skeletal muscles and other organs that can present at any age after normal development earlier in life. Its distinguishing features are myoclonus, generalized epilepsy, ataxia, myopathy and dementia. Short stature, optic atrophy, hearing loss, cardiomyopathy and peripheral neuropathy are all also common symptoms in individuals with MERRF. It can be ruled out in Lafora patients by examining cerebrospinal fluid concentrations or imaging spectroscopy for lactate. Pathogenic variants in mitochondrial genes cause MERRF. (For more information, choose “MERRF Syndrome” as your search term in the Rare Disease Database.)Subacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder characterized by encephalitis that develops as a result of measles infection. The initial infection typically occurs early in childhood and then lies dormant for 6-8 years before neurological symptoms begin. These symptoms can include cognitive decline, behavioral changes, myoclonic jerks, seizures and vision issues. SSPE can be ruled out in Lafora patients by examining measles antibody titers. (For more information, choose “Subacute Sclerosing Panencephalitis” as your search term in the Rare Disease Database.)
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Diagnosis of Lafora Disease
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The diagnostic process for individuals with Lafora disease can occur in multiple ways. The first symptoms that bring a patient to a physician are usually focal or myoclonic seizures. Neurological findings typically start at 8-19 years of age. Lafora disease can be diagnosed with a skin biopsy that shows Lafora bodies in the cells of a patient’s sweat ducts. Molecular genetic testing for pathogenic variants in the EPM2A or EPM2B genes confirms the diagnosis.Clinical Testing and Work-Up
Doctors may suggest an electroencephalogram (EEG) or magnetic resonance imaging (MRI) of the brain to check for other disorders and screen for seizures.
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Diagnosis of Lafora Disease. The diagnostic process for individuals with Lafora disease can occur in multiple ways. The first symptoms that bring a patient to a physician are usually focal or myoclonic seizures. Neurological findings typically start at 8-19 years of age. Lafora disease can be diagnosed with a skin biopsy that shows Lafora bodies in the cells of a patient’s sweat ducts. Molecular genetic testing for pathogenic variants in the EPM2A or EPM2B genes confirms the diagnosis.Clinical Testing and Work-Up
Doctors may suggest an electroencephalogram (EEG) or magnetic resonance imaging (MRI) of the brain to check for other disorders and screen for seizures.
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Therapies of Lafora Disease
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Treatment
There is no cure yet for Lafora disease, so current treatment is focused on managing symptoms.Medical care may involve a team of specialists, including a neurologist (a physician who specializes in the diagnosis and treatment of medical conditions affecting the brain and nervous system) and a geneticist (a physician who specializes in the diagnosis and treatment of genetic conditions). Physical therapy or occupational therapy may be considered to help maintain good muscular condition and preserve the ability to walk for as long as possible. Symptoms are typically managed using a combination of medications. Many different anti-seizure medications (ASM) are used to treat the seizures and myoclonus associated with Lafora disease, with some evidence for particular benefit from valproic acid and perampanel. Another type of medication that may be used are benzodiazepines. Seizure emergencies can involve myoclonic clusters (multiple jerking movements of a muscle or muscles) or myoclonic status epilepticus (myoclonic seizures that last for over 15 minutes); these emergencies may require urgent medical evaluation.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the patient and family may also be helpful.
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Therapies of Lafora Disease. Treatment
There is no cure yet for Lafora disease, so current treatment is focused on managing symptoms.Medical care may involve a team of specialists, including a neurologist (a physician who specializes in the diagnosis and treatment of medical conditions affecting the brain and nervous system) and a geneticist (a physician who specializes in the diagnosis and treatment of genetic conditions). Physical therapy or occupational therapy may be considered to help maintain good muscular condition and preserve the ability to walk for as long as possible. Symptoms are typically managed using a combination of medications. Many different anti-seizure medications (ASM) are used to treat the seizures and myoclonus associated with Lafora disease, with some evidence for particular benefit from valproic acid and perampanel. Another type of medication that may be used are benzodiazepines. Seizure emergencies can involve myoclonic clusters (multiple jerking movements of a muscle or muscles) or myoclonic status epilepticus (myoclonic seizures that last for over 15 minutes); these emergencies may require urgent medical evaluation.Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the patient and family may also be helpful.
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Overview of Lambert-Eaton Myasthenic Syndrome
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Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction. It is a miscommunication between the nerve cell and the muscles that lead to the gradual onset of muscle weakness. It starts in the proximal muscles of the legs or arms. LEMS can be categorized into two different classes: LEMS associated with small cell lung cancer (SCLC) and LEMS without cancer association. Approximately 60 percent of patients with LEMS have SCLC, and the onset of LEMS symptoms often precedes the detection of the cancer. LEMS patients with cancer tend to be older, mostly male, and nearly always have a long history of smoking. In patients in which there is no associated cancer, disease onset can be at any age and in males and females. LEMS may impact quality of life depending on the severity of symptoms.
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Overview of Lambert-Eaton Myasthenic Syndrome. Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder of the neuromuscular junction. It is a miscommunication between the nerve cell and the muscles that lead to the gradual onset of muscle weakness. It starts in the proximal muscles of the legs or arms. LEMS can be categorized into two different classes: LEMS associated with small cell lung cancer (SCLC) and LEMS without cancer association. Approximately 60 percent of patients with LEMS have SCLC, and the onset of LEMS symptoms often precedes the detection of the cancer. LEMS patients with cancer tend to be older, mostly male, and nearly always have a long history of smoking. In patients in which there is no associated cancer, disease onset can be at any age and in males and females. LEMS may impact quality of life depending on the severity of symptoms.
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Symptoms of Lambert-Eaton Myasthenic Syndrome
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LEMS is characterized by weakness and fatigue especially of the muscles in the legs and arms. The disease may affect the patient’s ability to engage in strenuous exercise and may make such activities as climbing stairs or walking up a steep walkway difficult. Onset is gradual, typically taking place over several weeks to many months. There is often a progression of symptoms whereby the shoulder muscles, muscles of the feet and hands, speech and swallowing muscles and eye muscles are affected in a stepwise fashion. The symptoms progress more quickly when LEMS is associated with cancer. Most LEMS patients also exhibit the following symptoms (sometimes called autonomic symptoms): dry mouth, dry eyes, constipation, impotence and decreased sweating. LEMS patients with or without cancer may also undergo significant weight loss. The tendon reflexes are diminished or absent on examination. In summary, LEMS is often described as a clinical “triad” of proximal muscle weakness, autonomic symptoms and reduced tendon reflexes.
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Symptoms of Lambert-Eaton Myasthenic Syndrome. LEMS is characterized by weakness and fatigue especially of the muscles in the legs and arms. The disease may affect the patient’s ability to engage in strenuous exercise and may make such activities as climbing stairs or walking up a steep walkway difficult. Onset is gradual, typically taking place over several weeks to many months. There is often a progression of symptoms whereby the shoulder muscles, muscles of the feet and hands, speech and swallowing muscles and eye muscles are affected in a stepwise fashion. The symptoms progress more quickly when LEMS is associated with cancer. Most LEMS patients also exhibit the following symptoms (sometimes called autonomic symptoms): dry mouth, dry eyes, constipation, impotence and decreased sweating. LEMS patients with or without cancer may also undergo significant weight loss. The tendon reflexes are diminished or absent on examination. In summary, LEMS is often described as a clinical “triad” of proximal muscle weakness, autonomic symptoms and reduced tendon reflexes.
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Causes of Lambert-Eaton Myasthenic Syndrome
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LEMS is an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. LEMS occurs because autoantibodies damage the “voltage-gated calcium channels (VGCC)” on the motor nerve membrane at the neuromuscular junction. These channels normally conduct calcium into the nerve resulting in the release of a chemical known as acetylcholine. Acetylcholine helps in the communication between nerve cells and muscles and is one of a group of chemicals known as neurotransmitters, which help to transmit nerve impulses. The autoantibodies attack the VGCC resulting in less acetylcholine release.In patients who have LEMS associated with cancer, the immune mediated response is initiated because VGCC is present on the surface of cancer cells and the immune system triggers the production of antibodies to fight off cancer cells. The idea is that autoantibodies created against the VGCC on the small cell lung cancer mistakenly attack the VGCC on the nerve membrane instead. One of the major risk factors for SCLC is smoking, and in patients who have LEMS associated with cancer, a long history of smoking is also a major contributing factor.In people who have LEMS not associated with cancer, genetic associations have been made with human leukocyte antigen (HLA) genotypes. HLA are proteins also present on the cell surface, and their function is to regulate the human immune system. However, it is unknown what causes these proteins to go awry array and trigger autoantibody production.
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Causes of Lambert-Eaton Myasthenic Syndrome. LEMS is an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons. LEMS occurs because autoantibodies damage the “voltage-gated calcium channels (VGCC)” on the motor nerve membrane at the neuromuscular junction. These channels normally conduct calcium into the nerve resulting in the release of a chemical known as acetylcholine. Acetylcholine helps in the communication between nerve cells and muscles and is one of a group of chemicals known as neurotransmitters, which help to transmit nerve impulses. The autoantibodies attack the VGCC resulting in less acetylcholine release.In patients who have LEMS associated with cancer, the immune mediated response is initiated because VGCC is present on the surface of cancer cells and the immune system triggers the production of antibodies to fight off cancer cells. The idea is that autoantibodies created against the VGCC on the small cell lung cancer mistakenly attack the VGCC on the nerve membrane instead. One of the major risk factors for SCLC is smoking, and in patients who have LEMS associated with cancer, a long history of smoking is also a major contributing factor.In people who have LEMS not associated with cancer, genetic associations have been made with human leukocyte antigen (HLA) genotypes. HLA are proteins also present on the cell surface, and their function is to regulate the human immune system. However, it is unknown what causes these proteins to go awry array and trigger autoantibody production.
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Affects of Lambert-Eaton Myasthenic Syndrome
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The estimated worldwide prevalence of LEMS is about 2.8 per million, making it a rare disease. There are approximately 400 known cases of LEMS in the United States. When LEMS is associated with SCLC, the patients tend to be older and are more likely to be male. The average age of onset of SCLC is around 60 years of age. Approximately 3% of SCLC patients develop LEMS, but clinical symptoms of LEMS usually precede the SCLC diagnosis (sometimes by many years). When LEMS is not related to cancer, the syndrome may occur at any age, and the typical onset is about 35 years of age. LEMS is extremely rare in the pediatric population, and there have only been 11 affected children reported in literature.
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Affects of Lambert-Eaton Myasthenic Syndrome. The estimated worldwide prevalence of LEMS is about 2.8 per million, making it a rare disease. There are approximately 400 known cases of LEMS in the United States. When LEMS is associated with SCLC, the patients tend to be older and are more likely to be male. The average age of onset of SCLC is around 60 years of age. Approximately 3% of SCLC patients develop LEMS, but clinical symptoms of LEMS usually precede the SCLC diagnosis (sometimes by many years). When LEMS is not related to cancer, the syndrome may occur at any age, and the typical onset is about 35 years of age. LEMS is extremely rare in the pediatric population, and there have only been 11 affected children reported in literature.
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Related disorders of Lambert-Eaton Myasthenic Syndrome
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Symptoms of the following disorders can be similar to those of Lambert-Eaton myasthenic syndrome. Comparisons may be useful for a differential diagnosis:Myasthenia gravis (MG) is a chronic neuromuscular disease characterized by weakness and abnormally rapid fatigue of the voluntary muscles, with improvement following rest. Any group of muscles may be affected, but those around the eyes and the muscles used for swallowing are the most commonly involved. Often, LEMS is misdiagnosed as MG because of the similarity in symptoms but there are key differences. In LEMS, eye muscle weakness, when present, tends to be mild and, unlike with MG, is almost never the only symptom of the disease. Severe respiratory muscle weakness, which can be fatal in MG, is rare in LEMS. The autonomic symptoms which affect most LEMS patients are not present in MG. For more information on this disorder, choose “myasthenia” as your search term in the Rare Disease Database.)Guillain-Barre syndrome is an autoimmune disease which occurs when the body’s defense system attacks the nerves, damaging the nerve’s myelin and axon. Nerve signals are delayed and altered, causing weakness and paralysis of the muscles of the legs, arms and other parts of the body. Abnormal sensations such as numbness or tingling also occur. If muscle nerves are damaged, the patient experiences aching and weak muscles, shortness of breath and difficulty in swallowing. If the autonomic nervous system is damaged, the patient may experience alterations of blood pressure, heart rate, vision, body temperature, bladder function and blood chemistries. (For more information on this disorder, choose “Guillain” as your search term in the Rare Disease Database.)
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Related disorders of Lambert-Eaton Myasthenic Syndrome. Symptoms of the following disorders can be similar to those of Lambert-Eaton myasthenic syndrome. Comparisons may be useful for a differential diagnosis:Myasthenia gravis (MG) is a chronic neuromuscular disease characterized by weakness and abnormally rapid fatigue of the voluntary muscles, with improvement following rest. Any group of muscles may be affected, but those around the eyes and the muscles used for swallowing are the most commonly involved. Often, LEMS is misdiagnosed as MG because of the similarity in symptoms but there are key differences. In LEMS, eye muscle weakness, when present, tends to be mild and, unlike with MG, is almost never the only symptom of the disease. Severe respiratory muscle weakness, which can be fatal in MG, is rare in LEMS. The autonomic symptoms which affect most LEMS patients are not present in MG. For more information on this disorder, choose “myasthenia” as your search term in the Rare Disease Database.)Guillain-Barre syndrome is an autoimmune disease which occurs when the body’s defense system attacks the nerves, damaging the nerve’s myelin and axon. Nerve signals are delayed and altered, causing weakness and paralysis of the muscles of the legs, arms and other parts of the body. Abnormal sensations such as numbness or tingling also occur. If muscle nerves are damaged, the patient experiences aching and weak muscles, shortness of breath and difficulty in swallowing. If the autonomic nervous system is damaged, the patient may experience alterations of blood pressure, heart rate, vision, body temperature, bladder function and blood chemistries. (For more information on this disorder, choose “Guillain” as your search term in the Rare Disease Database.)
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Diagnosis of Lambert-Eaton Myasthenic Syndrome
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Diagnosis of LEMS is based on clinical symptoms and signs. A few diagnostic testing methods are available to help diagnose LEMS. Electrophysiological studies are done to measure muscle response and muscle strength. Repetitive nerve stimulation measures the electrical activity of the muscle upon stimulation. Antibody testing is done to identify the presence of anti-VGCC antibodies.Electromyography results usually show a decrease in compound motor action potential (CMAP). Repetitive nerve stimulation initially shows a small amount of electrical activity in the muscle. After high frequency repetitive stimulation or exercise, there is increased activity in the muscle.Anti-VGCC antibodies are detectable in approximately 85% of LEMS patients and when detected they are highly specific for the condition. This is because anti- VGCC antibodies are found in LEMS with SCLC and in LEMS without cancer association.Screening for SCLC is a very important part of the diagnostic workup for LEMS. A chest CT (and sometimes FDG-PET) scan will usually form the basis of this screening. Depending on the risk profile, a negative initial screen will be repeated at suitable time intervals. A recently discovered tumor marker antibody directed against SOX, which is found in 65% of SCLC LEMS patients as opposed to only 5% of non-tumor LEMS patients, may help guide clinical practice in the future.
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Diagnosis of Lambert-Eaton Myasthenic Syndrome. Diagnosis of LEMS is based on clinical symptoms and signs. A few diagnostic testing methods are available to help diagnose LEMS. Electrophysiological studies are done to measure muscle response and muscle strength. Repetitive nerve stimulation measures the electrical activity of the muscle upon stimulation. Antibody testing is done to identify the presence of anti-VGCC antibodies.Electromyography results usually show a decrease in compound motor action potential (CMAP). Repetitive nerve stimulation initially shows a small amount of electrical activity in the muscle. After high frequency repetitive stimulation or exercise, there is increased activity in the muscle.Anti-VGCC antibodies are detectable in approximately 85% of LEMS patients and when detected they are highly specific for the condition. This is because anti- VGCC antibodies are found in LEMS with SCLC and in LEMS without cancer association.Screening for SCLC is a very important part of the diagnostic workup for LEMS. A chest CT (and sometimes FDG-PET) scan will usually form the basis of this screening. Depending on the risk profile, a negative initial screen will be repeated at suitable time intervals. A recently discovered tumor marker antibody directed against SOX, which is found in 65% of SCLC LEMS patients as opposed to only 5% of non-tumor LEMS patients, may help guide clinical practice in the future.
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Therapies of Lambert-Eaton Myasthenic Syndrome
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Treatment
Treatment of LEMS may vary depending upon the presence of associated cancer. If cancer is present, treatment first involves treatment directed at the cancer, and this alone may result in relief of LEMS symptoms.There is no cure for LEMS and treatment usually involves improving quality of life. Therefore, symptomatic treatment is the focus in the management of LEMS. The FDA recently approved a new drug for the symptomatic relief of symptoms associated with muscle weakness called amifampridine (Firdapse). It is a potassium channel blocker that works by increasing the release of acytelcholine. At this time, it is the only drug approved for the indication of LEMS. The medication has shown to have significant benefits such as improving muscle strength and CMAP. In addition, it is a well-tolerated medication.If Firdapse alone does not improve symptoms, there are additional options that can be added in case of symptom progression. Mestinon is indicated for the treatment of MG but is often used in combination with Firdapse to treat symptoms of autonomic dysfunction (dry mouth, dry eyes, constipation, impotence and decreased sweating). In patients with MG, Menstinon improves muscle strength, but in patients with LEMS, it has only shown to improve symptoms of autonomic dysfunction.In 2019, amifampridine (Ruzurgi) was approved to treat LEMS in patients 6 to under 17 years of age. This is the first FDA approved treatment specifically for pediatric patients with LEMS.Drugs that suppress the activity of the immune system (immunosuppressive drugs) are used in LEMS patients with more severe symptoms, e.g., prednisone (alone or in conjunction with azathioprine or cyclosporin). In some patients, a course of high dose immunoglobulins may prevent further disease progression.
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Therapies of Lambert-Eaton Myasthenic Syndrome. Treatment
Treatment of LEMS may vary depending upon the presence of associated cancer. If cancer is present, treatment first involves treatment directed at the cancer, and this alone may result in relief of LEMS symptoms.There is no cure for LEMS and treatment usually involves improving quality of life. Therefore, symptomatic treatment is the focus in the management of LEMS. The FDA recently approved a new drug for the symptomatic relief of symptoms associated with muscle weakness called amifampridine (Firdapse). It is a potassium channel blocker that works by increasing the release of acytelcholine. At this time, it is the only drug approved for the indication of LEMS. The medication has shown to have significant benefits such as improving muscle strength and CMAP. In addition, it is a well-tolerated medication.If Firdapse alone does not improve symptoms, there are additional options that can be added in case of symptom progression. Mestinon is indicated for the treatment of MG but is often used in combination with Firdapse to treat symptoms of autonomic dysfunction (dry mouth, dry eyes, constipation, impotence and decreased sweating). In patients with MG, Menstinon improves muscle strength, but in patients with LEMS, it has only shown to improve symptoms of autonomic dysfunction.In 2019, amifampridine (Ruzurgi) was approved to treat LEMS in patients 6 to under 17 years of age. This is the first FDA approved treatment specifically for pediatric patients with LEMS.Drugs that suppress the activity of the immune system (immunosuppressive drugs) are used in LEMS patients with more severe symptoms, e.g., prednisone (alone or in conjunction with azathioprine or cyclosporin). In some patients, a course of high dose immunoglobulins may prevent further disease progression.
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Overview of Lamellar Ichthyosis
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Summary Lamellar ichthyosis (LI) is a rare genetic skin disorder that is present at birth. It is one of three genetic skin disorders called autosomal recessive congenital ichthyoses (ARCI). The other two are known as harlequin ichthyosis and congenital ichthyosiform erythroderma. All ARCI conditions are considered a clinical spectrum. There is overlap in symptoms between ARCI conditions. In LI, the body creates skin cells at a normal rate. However, they do not separate from each other at the surface of the skin the way they should. In addition, the body does not shed the skin fast enough, causing brown scales to form.
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Overview of Lamellar Ichthyosis. Summary Lamellar ichthyosis (LI) is a rare genetic skin disorder that is present at birth. It is one of three genetic skin disorders called autosomal recessive congenital ichthyoses (ARCI). The other two are known as harlequin ichthyosis and congenital ichthyosiform erythroderma. All ARCI conditions are considered a clinical spectrum. There is overlap in symptoms between ARCI conditions. In LI, the body creates skin cells at a normal rate. However, they do not separate from each other at the surface of the skin the way they should. In addition, the body does not shed the skin fast enough, causing brown scales to form.
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Symptoms of Lamellar Ichthyosis
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Babies born with LI are sometimes called “collodion babies.” They are covered in a clear membrane (collodion) so it looks like they are covered with plastic wrap. Their skin can look red or dark, tight, and split. These newborns can have skin that is so tight that it forces their lips to turn outward. Also, the skin on their hands may be tight, preventing them from extending their fingers. Newborns can have problems regulating their body temperature and preventing water loss. They may also be more likely to develop skin infections. The collodion membrane is usually shed a few days to a few weeks after birth. Once this happens, the newborn is covered with broad, dark scales. The space in between the scales may be shallow or deep. Some people with LI cannot close their eyes because the skin is so tight. In some cases, the skin around the eyes pulls so tightly that it causes the eyelids to turn outward. It can lead to irritation of the inner eyelid and drying of the eyeball. Some doctors recommend surgery to prevent damage to the eyeball and vision problems. People with LI may also have thick nails and hair loss due to the thickness of the scales on their scalp. They may also have thick skin on the palms of the hands and soles of the feet.
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Symptoms of Lamellar Ichthyosis. Babies born with LI are sometimes called “collodion babies.” They are covered in a clear membrane (collodion) so it looks like they are covered with plastic wrap. Their skin can look red or dark, tight, and split. These newborns can have skin that is so tight that it forces their lips to turn outward. Also, the skin on their hands may be tight, preventing them from extending their fingers. Newborns can have problems regulating their body temperature and preventing water loss. They may also be more likely to develop skin infections. The collodion membrane is usually shed a few days to a few weeks after birth. Once this happens, the newborn is covered with broad, dark scales. The space in between the scales may be shallow or deep. Some people with LI cannot close their eyes because the skin is so tight. In some cases, the skin around the eyes pulls so tightly that it causes the eyelids to turn outward. It can lead to irritation of the inner eyelid and drying of the eyeball. Some doctors recommend surgery to prevent damage to the eyeball and vision problems. People with LI may also have thick nails and hair loss due to the thickness of the scales on their scalp. They may also have thick skin on the palms of the hands and soles of the feet.
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Causes of Lamellar Ichthyosis
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LI can be caused by harmful changes in several genes. The most common gene related to this condition is TGM1. Other genes include NIPAL4, ALOX12B, and CYP4F22. These genes provide the instructions to make enzymes and proteins. These enzymes and proteins are important for normal development, function, and shedding of skin cells. There is also evidence that more genes are related to LI. The severity of the condition cannot always be determined based on genetic testing results. The harmful changes that cause LI are recessively inherited. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and therefore have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Causes of Lamellar Ichthyosis. LI can be caused by harmful changes in several genes. The most common gene related to this condition is TGM1. Other genes include NIPAL4, ALOX12B, and CYP4F22. These genes provide the instructions to make enzymes and proteins. These enzymes and proteins are important for normal development, function, and shedding of skin cells. There is also evidence that more genes are related to LI. The severity of the condition cannot always be determined based on genetic testing results. The harmful changes that cause LI are recessively inherited. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and therefore have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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Lamellar Ichthyosis
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Affects of Lamellar Ichthyosis
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LI occurs in about one in 200,000 people. The condition can affect people of all genders, races, and ethnicities.
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Affects of Lamellar Ichthyosis. LI occurs in about one in 200,000 people. The condition can affect people of all genders, races, and ethnicities.
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Related disorders of Lamellar Ichthyosis
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Signs and symptoms of the following disorders may be like those of LI. “Ichthyoses” are a group of disorders that cause scaly skin. People with ichthyosis have a build-up of large amounts of dead skin cells on the top layer of the skin. This build up can be caused by defects in various structures in the skin. Skin cells known as “corneocytes” make up the outer layer of the skin. These cells are surrounded by proteins that make the skin strong and flexible. Corneocytes are also surrounded by a fat-rich matrix that waterproofs the skin. Corneocytes are connected to each other by proteins. The breakdown of these proteins is important for skin shedding. You can think of the skin cells as bricks, while the surrounding matrix is the mortar holding the cells together. When any of these skin structures are not working, a person can have ichthyosis. (See “Ichthyosis” in the Rare Disease Database.) Congenital ichthyosiform erythroderma (sometimes called collodion baby, ichthyosis congenita, xeroderma, or desquamation of the newborn) is a genetic skin disorder on the spectrum of ARCI. Symptoms include abnormally red, dry, and rough skin with large or fine white scales. The skin tends to feel itchy as well. Skin on the palms of the hands and soles of the feet can be very thick. (For more information, choose “Ichthyosis Congenita” as your search term in the Rare Disease Database.) X-linked ichthyosis is a genetic skin disorder that affects mostly males but can affect females. It is caused when people do not have enough of the enzyme steroid sulfatase. Symptoms include brownish scales on the back of the neck, back, and legs. There are other conditions where ichthyosis is a symptom. However, many of these conditions are syndromic and have other symptoms that do not affect the skin. These symptoms can include cognitive disabilities, nervous system problems, and arm/leg shortening.
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Related disorders of Lamellar Ichthyosis. Signs and symptoms of the following disorders may be like those of LI. “Ichthyoses” are a group of disorders that cause scaly skin. People with ichthyosis have a build-up of large amounts of dead skin cells on the top layer of the skin. This build up can be caused by defects in various structures in the skin. Skin cells known as “corneocytes” make up the outer layer of the skin. These cells are surrounded by proteins that make the skin strong and flexible. Corneocytes are also surrounded by a fat-rich matrix that waterproofs the skin. Corneocytes are connected to each other by proteins. The breakdown of these proteins is important for skin shedding. You can think of the skin cells as bricks, while the surrounding matrix is the mortar holding the cells together. When any of these skin structures are not working, a person can have ichthyosis. (See “Ichthyosis” in the Rare Disease Database.) Congenital ichthyosiform erythroderma (sometimes called collodion baby, ichthyosis congenita, xeroderma, or desquamation of the newborn) is a genetic skin disorder on the spectrum of ARCI. Symptoms include abnormally red, dry, and rough skin with large or fine white scales. The skin tends to feel itchy as well. Skin on the palms of the hands and soles of the feet can be very thick. (For more information, choose “Ichthyosis Congenita” as your search term in the Rare Disease Database.) X-linked ichthyosis is a genetic skin disorder that affects mostly males but can affect females. It is caused when people do not have enough of the enzyme steroid sulfatase. Symptoms include brownish scales on the back of the neck, back, and legs. There are other conditions where ichthyosis is a symptom. However, many of these conditions are syndromic and have other symptoms that do not affect the skin. These symptoms can include cognitive disabilities, nervous system problems, and arm/leg shortening.
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Lamellar Ichthyosis
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Diagnosis of Lamellar Ichthyosis
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Diagnosis of Lamellar Ichthyosis.
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Therapies of Lamellar Ichthyosis
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Treatment
LI is usually treated topically. Doctors use creams that help repair the skin barrier. These creams often contain ceramides or cholesterol. Moisturizers with petrolatum or lanolin may also be used. Sometimes, mild keratolytics or topical retinoids are used as treatment options. Doctors may treat severe LI with oral retinoids. Retinoids can be toxic to the body, so they are used with caution.To diagnose and treat ARCI, including LI, people may need to see the following medical specialists:Tests for temperature regulation problems and water loss as well as tests for infection may be needed.
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Therapies of Lamellar Ichthyosis. Treatment
LI is usually treated topically. Doctors use creams that help repair the skin barrier. These creams often contain ceramides or cholesterol. Moisturizers with petrolatum or lanolin may also be used. Sometimes, mild keratolytics or topical retinoids are used as treatment options. Doctors may treat severe LI with oral retinoids. Retinoids can be toxic to the body, so they are used with caution.To diagnose and treat ARCI, including LI, people may need to see the following medical specialists:Tests for temperature regulation problems and water loss as well as tests for infection may be needed.
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Overview of Landau Kleffner Syndrome
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Landau Kleffner syndrome (LKS) is a rare childhood disorder characterized by the loss of language comprehension (auditory verbal agnosia) and verbal expression (aphasia) in association with severely abnormal electroencephalographic (EEG) findings during sleep and clinical seizures in most patients.In 2022, the International League Against Epilepsy (ILAE) recommended that Landau-Kleffner syndrome be considered a subtype of developmental/epileptic encephalopathy with spike wave activation on sleep (DEE-SWAS). These conditions are a spectrum of epilepsy syndromes in children characterized by a specific abnormal EEG pattern and variable degrees of cognitive regression. A child with a diagnosis of LKS may transition to another DEE-SWAS syndrome over time.
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Overview of Landau Kleffner Syndrome. Landau Kleffner syndrome (LKS) is a rare childhood disorder characterized by the loss of language comprehension (auditory verbal agnosia) and verbal expression (aphasia) in association with severely abnormal electroencephalographic (EEG) findings during sleep and clinical seizures in most patients.In 2022, the International League Against Epilepsy (ILAE) recommended that Landau-Kleffner syndrome be considered a subtype of developmental/epileptic encephalopathy with spike wave activation on sleep (DEE-SWAS). These conditions are a spectrum of epilepsy syndromes in children characterized by a specific abnormal EEG pattern and variable degrees of cognitive regression. A child with a diagnosis of LKS may transition to another DEE-SWAS syndrome over time.
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Symptoms of Landau Kleffner Syndrome
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The symptoms typically begin between the ages of three and seven years although the condition may rarely occur in children as young as 18 months of age. Affected children often appear to have acquired deafness since they fail to respond to verbal language and in some cases to nonverbal sounds. A significant minority of children with LKS also develops serious behavioral dysfunction, including hyperactivity, temper outbursts, or withdrawn behaviors but rarely the severe social impairments seen in autism spectrum disorders.Approximately 70% of affected children have obvious seizures, most often focal with or without alteration of awareness and/or atypical absence in type.
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Symptoms of Landau Kleffner Syndrome. The symptoms typically begin between the ages of three and seven years although the condition may rarely occur in children as young as 18 months of age. Affected children often appear to have acquired deafness since they fail to respond to verbal language and in some cases to nonverbal sounds. A significant minority of children with LKS also develops serious behavioral dysfunction, including hyperactivity, temper outbursts, or withdrawn behaviors but rarely the severe social impairments seen in autism spectrum disorders.Approximately 70% of affected children have obvious seizures, most often focal with or without alteration of awareness and/or atypical absence in type.
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Causes of Landau Kleffner Syndrome
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The cause of Landau-Kleffner syndrome is unknown although a spectrum of epileptic conditions including LKS has been described in individuals with GRIN2A gene mutations and other candidate genes including RELN, BSN, EPHB2 and NID2 have been suggested. The response in some patients to immunosuppression has raised the question of autoimmune and other inflammatory mechanisms as potential contributors.
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Causes of Landau Kleffner Syndrome. The cause of Landau-Kleffner syndrome is unknown although a spectrum of epileptic conditions including LKS has been described in individuals with GRIN2A gene mutations and other candidate genes including RELN, BSN, EPHB2 and NID2 have been suggested. The response in some patients to immunosuppression has raised the question of autoimmune and other inflammatory mechanisms as potential contributors.
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Affects of Landau Kleffner Syndrome
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Landau-Kleffner syndrome is a rare disorder that affects twice as many males as females. Affected siblings and discordant monozygotic twins have been reported rarely.
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Affects of Landau Kleffner Syndrome. Landau-Kleffner syndrome is a rare disorder that affects twice as many males as females. Affected siblings and discordant monozygotic twins have been reported rarely.
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Related disorders of Landau Kleffner Syndrome
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Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental condition typically appearing before the age of thirty months. They are characterized by impairments in social communication and severely restricted interests or repetitive patterns of behavior. A significant minority of affected children have a history of developmental regression affecting language, social and behavioral functioning, which usually occurs between 18 and 30 months of age. Between 30-40 percent of children with ASDs have low scores on standardized intelligence tests. The clinical expression and severity of ASDs vary widely. The functional outcomes of those with ASDs are improved with intensive behavioral and developmental interventions beginning in early life. Rett syndrome is a rare neurodevelopmental condition associated with a known gene mutation. It occurs almost exclusively in females but can occur very rarely in males. Infants and children with the disorder typically develop normally until between 7 and 18 months of age, when they experience developmental regression affecting purposeful hand movements and verbal communication. Associated abnormalities typically include slowing of head growth (acquired microcephaly); development of distinctive, repetitive hand movements such as hand clapping, rubbing, or “wringing”; and loss of control of voluntary movements required for coordination of walking (gait apraxia). Affected children also typically develop breathing irregularities, feeding and swallowing difficulties, growth retardation, and seizures.Rett syndrome results from a mutation (change) in the MECP2 gene on the X chromosome. Most cases are thought to represent new mutations that occur spontaneously (sporadically) for unknown reasons. The MECP2 gene is known to play an essential role in the development of normal brain connections (synapses) and circuit formation. (For more information on this disorder, choose “Rett” as your search term in the Rare Disease Database).The following disorder may be associated with Landau-Kleffner syndrome as a secondary characteristic. It is not necessary for a differential diagnosis:Epilepsy is a collective term given to a group of disorders of the central nervous system characterized by repeated seizures which are manifest by observable changes in consciousness, muscle activity or other neurological functions caused by electrochemical disturbances in the brain. The major symptoms include loss of consciousness, convulsions, body-jerking, sensory loss, confusion, and disturbances of involuntary body functions (autonomic nervous system). EEGs often show characteristic patterns of electrical discharge even in-between the clinical episodes. There are many different forms of epilepsy including primary generalized which can manifest by convulsive motor movements or staring unresponsiveness and focal seizures which may be preceded by an “aura”, sometimes described as a feeling of vague discomfort or change in sensation followed by varying combinations of motor and sensory alterations. (For more information on this disorder, choose “Epilepsy” as your search term in the Rare Disease Database.)
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Related disorders of Landau Kleffner Syndrome. Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental condition typically appearing before the age of thirty months. They are characterized by impairments in social communication and severely restricted interests or repetitive patterns of behavior. A significant minority of affected children have a history of developmental regression affecting language, social and behavioral functioning, which usually occurs between 18 and 30 months of age. Between 30-40 percent of children with ASDs have low scores on standardized intelligence tests. The clinical expression and severity of ASDs vary widely. The functional outcomes of those with ASDs are improved with intensive behavioral and developmental interventions beginning in early life. Rett syndrome is a rare neurodevelopmental condition associated with a known gene mutation. It occurs almost exclusively in females but can occur very rarely in males. Infants and children with the disorder typically develop normally until between 7 and 18 months of age, when they experience developmental regression affecting purposeful hand movements and verbal communication. Associated abnormalities typically include slowing of head growth (acquired microcephaly); development of distinctive, repetitive hand movements such as hand clapping, rubbing, or “wringing”; and loss of control of voluntary movements required for coordination of walking (gait apraxia). Affected children also typically develop breathing irregularities, feeding and swallowing difficulties, growth retardation, and seizures.Rett syndrome results from a mutation (change) in the MECP2 gene on the X chromosome. Most cases are thought to represent new mutations that occur spontaneously (sporadically) for unknown reasons. The MECP2 gene is known to play an essential role in the development of normal brain connections (synapses) and circuit formation. (For more information on this disorder, choose “Rett” as your search term in the Rare Disease Database).The following disorder may be associated with Landau-Kleffner syndrome as a secondary characteristic. It is not necessary for a differential diagnosis:Epilepsy is a collective term given to a group of disorders of the central nervous system characterized by repeated seizures which are manifest by observable changes in consciousness, muscle activity or other neurological functions caused by electrochemical disturbances in the brain. The major symptoms include loss of consciousness, convulsions, body-jerking, sensory loss, confusion, and disturbances of involuntary body functions (autonomic nervous system). EEGs often show characteristic patterns of electrical discharge even in-between the clinical episodes. There are many different forms of epilepsy including primary generalized which can manifest by convulsive motor movements or staring unresponsiveness and focal seizures which may be preceded by an “aura”, sometimes described as a feeling of vague discomfort or change in sensation followed by varying combinations of motor and sensory alterations. (For more information on this disorder, choose “Epilepsy” as your search term in the Rare Disease Database.)
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Landau Kleffner Syndrome
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Diagnosis of Landau Kleffner Syndrome
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In additional to language regression, the diagnosis requires the presence of severely epileptiform activity on EEG, particularly during non-REM sleep. Additional testing may include magnetoencephalography. Brain imaging with magnetic resonance imaging (MRI) is recommended to exclude structural lesions since several cases have resulted from brain tumors. Other testing including behavioral and/or brainstem evoked audiometry and standardized psychometric and speech/language testing are helpful to exclude hearing loss and provide the basis for therapies to aide in recovery.
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Diagnosis of Landau Kleffner Syndrome. In additional to language regression, the diagnosis requires the presence of severely epileptiform activity on EEG, particularly during non-REM sleep. Additional testing may include magnetoencephalography. Brain imaging with magnetic resonance imaging (MRI) is recommended to exclude structural lesions since several cases have resulted from brain tumors. Other testing including behavioral and/or brainstem evoked audiometry and standardized psychometric and speech/language testing are helpful to exclude hearing loss and provide the basis for therapies to aide in recovery.
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Landau Kleffner Syndrome
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Therapies of Landau Kleffner Syndrome
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Treatment
The standard therapeutic approach begins with antiepileptic drugs, particularly “spike-suppressing” medications such as divalproex, ethosuximide, levitiracetam, and benzodiazepines. Some authors have suggested using a combination of corticosteroids and pulse benzodiazepines. Other antiepileptic drugs that may be beneficial are lamotrigine and felbamate.A supportive team approach for children with Landau-Kleffner syndrome may help to reestablish some communication skills. Appropriate speech and language therapy is important for affected children. Augmentative and alternative communication devices and even sign language training may be useful for some affected children with little or no understanding of language. Special education classes for children with severe speech and language disorders may prove beneficial as well.
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Therapies of Landau Kleffner Syndrome. Treatment
The standard therapeutic approach begins with antiepileptic drugs, particularly “spike-suppressing” medications such as divalproex, ethosuximide, levitiracetam, and benzodiazepines. Some authors have suggested using a combination of corticosteroids and pulse benzodiazepines. Other antiepileptic drugs that may be beneficial are lamotrigine and felbamate.A supportive team approach for children with Landau-Kleffner syndrome may help to reestablish some communication skills. Appropriate speech and language therapy is important for affected children. Augmentative and alternative communication devices and even sign language training may be useful for some affected children with little or no understanding of language. Special education classes for children with severe speech and language disorders may prove beneficial as well.
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Landau Kleffner Syndrome
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Overview of Langerhans Cell Histiocytosis
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SummaryLangerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia caused by alterations (mutations) of several genes in the MAPKinase pathway (MAPK). Important studies published from 2010 to 2021 have immensely clarified the biology of LCH. (Allen, Badalian-Very, Berres, Chakrobarty, Hogsted, Biggenwald) The cell of origin is a white blood cell known as a dendritic cell, although the historic designation of histiocyte is still used. (Allen 2010) The mutations BRAFV600E, MAP2K, and others) cause these dendritic cells to attract other white blood cells (lymphocytes, macrophages, and eosinophils) and cause a “lesion” in any organ of the body except the heart and kidneys. The mutation creates biologic changes in the histiocytes which prevent cell death and cause the disease cells to stay in a lesion. (Hogsted) These cells are also resistant to chemotherapy because of senescence (a “slumber-like state) (Biggenwald). Lymphocytes gathered in the lesions are ineffective at fighting malignant cells and also blunt the effect of chemotherapy. (Sengal) Children or adults may have LCH in skin (macular, papular, ulcerative, or seborrheic rashes), bones (painful lytic lesions), lymph nodes, brain (pituitary, cerebrum and cerebellum) lung, liver, spleen, and bone marrow. Systemic symptoms may include fever, bone pain, weight loss, draining ears, jaundice, diabetes insipidus or other diseases of the endocrine glands and malaise (a general feeling of ill-health).IntroductionThe preferred name for the condition is Langerhans cell histiocytosis as the dendritic cell which causes the disease has microscopic and cell surface characteristics like the dendritic Langerhans cell in the skin.
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Overview of Langerhans Cell Histiocytosis. SummaryLangerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia caused by alterations (mutations) of several genes in the MAPKinase pathway (MAPK). Important studies published from 2010 to 2021 have immensely clarified the biology of LCH. (Allen, Badalian-Very, Berres, Chakrobarty, Hogsted, Biggenwald) The cell of origin is a white blood cell known as a dendritic cell, although the historic designation of histiocyte is still used. (Allen 2010) The mutations BRAFV600E, MAP2K, and others) cause these dendritic cells to attract other white blood cells (lymphocytes, macrophages, and eosinophils) and cause a “lesion” in any organ of the body except the heart and kidneys. The mutation creates biologic changes in the histiocytes which prevent cell death and cause the disease cells to stay in a lesion. (Hogsted) These cells are also resistant to chemotherapy because of senescence (a “slumber-like state) (Biggenwald). Lymphocytes gathered in the lesions are ineffective at fighting malignant cells and also blunt the effect of chemotherapy. (Sengal) Children or adults may have LCH in skin (macular, papular, ulcerative, or seborrheic rashes), bones (painful lytic lesions), lymph nodes, brain (pituitary, cerebrum and cerebellum) lung, liver, spleen, and bone marrow. Systemic symptoms may include fever, bone pain, weight loss, draining ears, jaundice, diabetes insipidus or other diseases of the endocrine glands and malaise (a general feeling of ill-health).IntroductionThe preferred name for the condition is Langerhans cell histiocytosis as the dendritic cell which causes the disease has microscopic and cell surface characteristics like the dendritic Langerhans cell in the skin.
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Symptoms of Langerhans Cell Histiocytosis
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LCH is a disorder presenting in either single or multiple locations and thus causing a variety of signs and symptoms from mild to life-threatening. Single system presentations may be exclusively in the skin, bone, pituitary, or lungs. Patients affected in multiple systems most often have skin and bone involvement with any combination of other sites. When the liver, spleen, and bone marrow are involved, these patients are given the designation “high risk” which means the chance of death is approximately 15%. All patients with LCH in sites other than the bone marrow, spleen, and liver can be cured. (Gadner, Allen 2015)Bone involvement in children or adults presents as painful areas which may be swollen. In children, the skull is most often affected, followed by long bones of the upper and lower extremity, ribs and spine. When the temporal bones or mastoids are affected the patient may lose their hearing. These patients may present with pus draining from the ears and thought to have an infection. Other complications include fractures of long bones and compression of vertebrae causing extreme pain and possibly spinal cord damage. LCH in the mastoid, orbital, sphenoid and temporal bones are considered “CNS Risk” because of increased incidence of pituitary and brain involvement. Jaw involvement in children may result in early eruption of teeth as well as swollen and bleeding gums. Adults are more likely to have lesions in the mandible and maxilla with resulting loss of teeth.Patients may have skin involvement with extensive seborrhia-like rashes on the scalp that mimic persistent cradle cap; an erythematous papular rash similar to Candida diaper rash; or deep ulcerative lesions in the groin or arm pits or purplish-brown lesions 3-6mm in diameter which are often mistaken for a viral infection. Many adult female patients have ulcerative lesions in the genitalia. LCH lesions on the tongue, gums, and inside the cheeks can resemble cold sores. It is very important that children presenting with skin LCH have a complete evaluation to ensure there is no other disease site. (Simko 2014 J.Peds.) Infiltration of the liver and spleen causes massive abnormal enlargement of organs (organomegaly). Liver dysfunction causes hypoproteinemia with swelling of the arms and legs or abdomen. Patients may also have jaundice (yellow color to the skin and the white part of the eyes). Lymph nodes in the cervical, axillary, and inguinal areas are most often affected, but mediastinal nodes may enlarge causing wheezing and respiratory compromise.Lung involvement results in rapid breathing and leakage of air around the lung (pneumorthorax). (Vassalo, Ronceray) Pulmonary LCH is more prevalent in adults because of the association with smoking. Coughing up blood (hemoptysis) is rare. Intestinal infiltration leads to crampy pain and diarrhea, often with blood in it.LCH in the bone marrow causes pancytopenia, but thrombocytopenia is often the most obvious problem with bleeding and anemia that may be exacerbated by an enlarged spleen.Endocrine abnormalities from LCH include excessive thirst and urination caused by damage to the back part of the pituitary gland. (Donadieu 2004) This condition is known as diabetes insipidus. (Prosch) If the front part of the pituitary gland is damaged by LCH, the patient may have low levels of thyroid hormone, growth hormone, adrenal stimulating hormone and the hormones that lead to sexual maturation.Patients with cerebellar involvement present with difficulty walking or with balance (ataxia), tremors of their hands with difficulty writing (dysmetria), trouble speaking (dysarthria) as well as difficulty learning and having abnormal behaviors. (Wnorowski), Mittheisz)
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Symptoms of Langerhans Cell Histiocytosis. LCH is a disorder presenting in either single or multiple locations and thus causing a variety of signs and symptoms from mild to life-threatening. Single system presentations may be exclusively in the skin, bone, pituitary, or lungs. Patients affected in multiple systems most often have skin and bone involvement with any combination of other sites. When the liver, spleen, and bone marrow are involved, these patients are given the designation “high risk” which means the chance of death is approximately 15%. All patients with LCH in sites other than the bone marrow, spleen, and liver can be cured. (Gadner, Allen 2015)Bone involvement in children or adults presents as painful areas which may be swollen. In children, the skull is most often affected, followed by long bones of the upper and lower extremity, ribs and spine. When the temporal bones or mastoids are affected the patient may lose their hearing. These patients may present with pus draining from the ears and thought to have an infection. Other complications include fractures of long bones and compression of vertebrae causing extreme pain and possibly spinal cord damage. LCH in the mastoid, orbital, sphenoid and temporal bones are considered “CNS Risk” because of increased incidence of pituitary and brain involvement. Jaw involvement in children may result in early eruption of teeth as well as swollen and bleeding gums. Adults are more likely to have lesions in the mandible and maxilla with resulting loss of teeth.Patients may have skin involvement with extensive seborrhia-like rashes on the scalp that mimic persistent cradle cap; an erythematous papular rash similar to Candida diaper rash; or deep ulcerative lesions in the groin or arm pits or purplish-brown lesions 3-6mm in diameter which are often mistaken for a viral infection. Many adult female patients have ulcerative lesions in the genitalia. LCH lesions on the tongue, gums, and inside the cheeks can resemble cold sores. It is very important that children presenting with skin LCH have a complete evaluation to ensure there is no other disease site. (Simko 2014 J.Peds.) Infiltration of the liver and spleen causes massive abnormal enlargement of organs (organomegaly). Liver dysfunction causes hypoproteinemia with swelling of the arms and legs or abdomen. Patients may also have jaundice (yellow color to the skin and the white part of the eyes). Lymph nodes in the cervical, axillary, and inguinal areas are most often affected, but mediastinal nodes may enlarge causing wheezing and respiratory compromise.Lung involvement results in rapid breathing and leakage of air around the lung (pneumorthorax). (Vassalo, Ronceray) Pulmonary LCH is more prevalent in adults because of the association with smoking. Coughing up blood (hemoptysis) is rare. Intestinal infiltration leads to crampy pain and diarrhea, often with blood in it.LCH in the bone marrow causes pancytopenia, but thrombocytopenia is often the most obvious problem with bleeding and anemia that may be exacerbated by an enlarged spleen.Endocrine abnormalities from LCH include excessive thirst and urination caused by damage to the back part of the pituitary gland. (Donadieu 2004) This condition is known as diabetes insipidus. (Prosch) If the front part of the pituitary gland is damaged by LCH, the patient may have low levels of thyroid hormone, growth hormone, adrenal stimulating hormone and the hormones that lead to sexual maturation.Patients with cerebellar involvement present with difficulty walking or with balance (ataxia), tremors of their hands with difficulty writing (dysmetria), trouble speaking (dysarthria) as well as difficulty learning and having abnormal behaviors. (Wnorowski), Mittheisz)
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Causes of Langerhans Cell Histiocytosis
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LCH is caused by mutations in a cell signaling pathway known as the MAPKinase pathway. Key genes mutated in this pathway include BRAF (65-70%), MAP2K (20%), and other rarer genes, all of which lead to abnormal activation of a gene known as ERK. (Durham) These mutations are “genetic accidents” which occur during DNA copying in dendritic cells and are not inherited. The maturation stage of the dendritic cell will determine what type of disease a patient will develop. If the mutation occurs when the dendritic cell is still in stem cell stage, this early precursor may go to any organ in the body-especially liver, spleen and bone marrow. Mutation in a more mature dendritic cell will lead to LCH in a variety of organs, but not the “high risk” ones mentioned before. An even more mature dendritic cell carrying this mutation may go to only skin and bone.Family members of LCH patients have a higher incidence of thyroid disease. Smoking is strongly associated with lung LCH.
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Causes of Langerhans Cell Histiocytosis. LCH is caused by mutations in a cell signaling pathway known as the MAPKinase pathway. Key genes mutated in this pathway include BRAF (65-70%), MAP2K (20%), and other rarer genes, all of which lead to abnormal activation of a gene known as ERK. (Durham) These mutations are “genetic accidents” which occur during DNA copying in dendritic cells and are not inherited. The maturation stage of the dendritic cell will determine what type of disease a patient will develop. If the mutation occurs when the dendritic cell is still in stem cell stage, this early precursor may go to any organ in the body-especially liver, spleen and bone marrow. Mutation in a more mature dendritic cell will lead to LCH in a variety of organs, but not the “high risk” ones mentioned before. An even more mature dendritic cell carrying this mutation may go to only skin and bone.Family members of LCH patients have a higher incidence of thyroid disease. Smoking is strongly associated with lung LCH.
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Affects of Langerhans Cell Histiocytosis
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Hispanics have a higher incidence of diffuse LCH involvement and Blacks are less affected than Whites. (Riberio) The overall incidence of LCH is between 4 and 9 cases per million with males slightly more affected than females (1.2:1) and the highest number of cases presenting in the first four years of life. The incidence is adults is not known, but may be 1-2 per million.
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Affects of Langerhans Cell Histiocytosis. Hispanics have a higher incidence of diffuse LCH involvement and Blacks are less affected than Whites. (Riberio) The overall incidence of LCH is between 4 and 9 cases per million with males slightly more affected than females (1.2:1) and the highest number of cases presenting in the first four years of life. The incidence is adults is not known, but may be 1-2 per million.
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Related disorders of Langerhans Cell Histiocytosis
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Symptoms of the following disorders can be similar to those of Langerhans cell histiocytosis. Comparisons may be useful for a differential diagnosis:Rosai-Dorfman disease (RDD) is a rare disorder characterized by overproduction) and accumulation of a specific type of white blood cell (macrophage/histiocyte) in the lymph nodes of the body (lymphadenopathy), most often those of the neck (cervical lymphadenopathy). In some patients, abnormal accumulation of histiocytes (macrophages) may occur in other areas of the body besides the lymph nodes (extranodal). These areas include the skin, central nervous system, kidney, and digestive tract. The symptoms and physical findings associated with RDD vary depending upon the specific areas of the body that are affected. The disorder predominantly affects children, adolescents or young adults. Some RDD patients have KRAS and MAP2K mutations, but many have none. The diagnosis of RDD is made by finding excessive numbers of histiocytes that often have lymphocytes passing through their cytoplasm. (For more information on this disorder, choose “Rosai-Dorfman” as your search term in the Rare Disease Database.)Juvenile xanthogranuloma (JXG) belongs to the family of histiocytic diseases including LCH and may sometimes be confused with LCH. Some LCH patients have scattered JXG cells in their lesions. The typical skin rash of JXG is a flesh-colored or brownish-purple macule or papule with a single or only a few lesions found anywhere on the body. Some patients have many lesions. JXG may also affect the liver, spleen, kidney, brain, or bones. Mutations of MAP2K, CSF1R, KRAS, NRAS, KIT, and several others have been described. (Durham) Erdheim-Chester disease (ECD) is caused by mutations of the MAPK pathway, most often the BRAF V600E, MAPK, KRAS, and NRAS mutations. ECD is characterized by excessive accumulation of fibrous/histiocytic infiltrates in and around multiple tissues often affecting the lungs, heart, and kidneys by forming “rinds” or sheaths around these organs. (Goyal) Other ECD sites include the long bones with increased density (sclerosis) in the femur or tibiae (upper or lower leg bones), skin rashes, tissues behind the eyeballs, and masses in the pituitary gland or brain. Associated symptoms and findings and disease course depend on the specific location and extent of such involvement. (For more information on this disorder, choose “Erdheim-Chester” as your search term in the Rare Disease Database.)Seborrheic dermatitis is a skin disorder characterized by reddish, scaly patches affecting the scalp. The disorder may spread to affect the neck, face, and other areas of the body. Individuals with LCH that present with skin symptoms may be misdiagnosed with seborrheic dermatitis. The exact cause of seborrheic dermatitis is not known.
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Related disorders of Langerhans Cell Histiocytosis. Symptoms of the following disorders can be similar to those of Langerhans cell histiocytosis. Comparisons may be useful for a differential diagnosis:Rosai-Dorfman disease (RDD) is a rare disorder characterized by overproduction) and accumulation of a specific type of white blood cell (macrophage/histiocyte) in the lymph nodes of the body (lymphadenopathy), most often those of the neck (cervical lymphadenopathy). In some patients, abnormal accumulation of histiocytes (macrophages) may occur in other areas of the body besides the lymph nodes (extranodal). These areas include the skin, central nervous system, kidney, and digestive tract. The symptoms and physical findings associated with RDD vary depending upon the specific areas of the body that are affected. The disorder predominantly affects children, adolescents or young adults. Some RDD patients have KRAS and MAP2K mutations, but many have none. The diagnosis of RDD is made by finding excessive numbers of histiocytes that often have lymphocytes passing through their cytoplasm. (For more information on this disorder, choose “Rosai-Dorfman” as your search term in the Rare Disease Database.)Juvenile xanthogranuloma (JXG) belongs to the family of histiocytic diseases including LCH and may sometimes be confused with LCH. Some LCH patients have scattered JXG cells in their lesions. The typical skin rash of JXG is a flesh-colored or brownish-purple macule or papule with a single or only a few lesions found anywhere on the body. Some patients have many lesions. JXG may also affect the liver, spleen, kidney, brain, or bones. Mutations of MAP2K, CSF1R, KRAS, NRAS, KIT, and several others have been described. (Durham) Erdheim-Chester disease (ECD) is caused by mutations of the MAPK pathway, most often the BRAF V600E, MAPK, KRAS, and NRAS mutations. ECD is characterized by excessive accumulation of fibrous/histiocytic infiltrates in and around multiple tissues often affecting the lungs, heart, and kidneys by forming “rinds” or sheaths around these organs. (Goyal) Other ECD sites include the long bones with increased density (sclerosis) in the femur or tibiae (upper or lower leg bones), skin rashes, tissues behind the eyeballs, and masses in the pituitary gland or brain. Associated symptoms and findings and disease course depend on the specific location and extent of such involvement. (For more information on this disorder, choose “Erdheim-Chester” as your search term in the Rare Disease Database.)Seborrheic dermatitis is a skin disorder characterized by reddish, scaly patches affecting the scalp. The disorder may spread to affect the neck, face, and other areas of the body. Individuals with LCH that present with skin symptoms may be misdiagnosed with seborrheic dermatitis. The exact cause of seborrheic dermatitis is not known.
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Diagnosis of Langerhans Cell Histiocytosis
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The diagnostic work-up may include X-rays of the skull, a complete skeletal bone survey and PET scan, chest x-ray, complete blood count and differential, erythrocyte sedimentation rate, liver function tests including AST, ALT, bilirubin, and albumin; electrolytes and urinalysis. (Phillips) CT of the skull if mastoids, orbits, or sphenoid are involved. Pulmonary disease: high resolution CT. A brain MRI is needed for patients with pituitary or suspicion of other brain lesions. When symptoms of diabetes insipidus occur, a water deprivation test or serum and urine osmolality is required.
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Diagnosis of Langerhans Cell Histiocytosis. The diagnostic work-up may include X-rays of the skull, a complete skeletal bone survey and PET scan, chest x-ray, complete blood count and differential, erythrocyte sedimentation rate, liver function tests including AST, ALT, bilirubin, and albumin; electrolytes and urinalysis. (Phillips) CT of the skull if mastoids, orbits, or sphenoid are involved. Pulmonary disease: high resolution CT. A brain MRI is needed for patients with pituitary or suspicion of other brain lesions. When symptoms of diabetes insipidus occur, a water deprivation test or serum and urine osmolality is required.
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Therapies of Langerhans Cell Histiocytosis
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LCHSingle bone lesions (not in the CNS risk group) are treated with surgery alone or with injection of steroids.CNS Risk bone lesions are treated with Velban and prednisone or cytarabine alone.Multifocal bone or multifocal low risk lesions are treated with Velban/prednisone or cytarabine alone (Gadner, Simko 2015).Multifocal High Risk lesions are treated with Velban/prednisone/6MP or cytarabine alone.If only skin lesions are present and not extensive, treatment may not be necessary. If treatment is needed, hydroxyurea alone or with methotrexate is very effective. (Zinn) Oral methotrexate or thalidomide are also used (McClain 2007). Topical ointments and PUVA are not very effective.Central nervous system involvement (pituitary or other mass lesions) is treated with cytarabine, cladribine, or MAPK inhibitors (McClain 2018).Neurodegenerative syndrome is treated with cytarabine or MAPK inhibitors (McClain 2018).If a patient does not respond to the standard therapy by the sixth week (or twelfth week for a partial response) they should be changed to the salvage therapy (Cytarabine, Cladribine, Cladribine/cytarabine, Clofarabine, or a MAPK inhibitor) (Simko 2015, Weitzman, Donadieu 2015, Simko 2014 Ped Blood Cancer, Eckstein).Adults should not be treated with Velban and prednisone because these drugs are not effective and cause excessive toxicity. Cytarabine has been shown to be a better therapy and cladribine has also been effective (Cantu). Oral hydroxyurea with or without oral methotrexate has been effective in treating skin and bone LCH, with special efficacy for vaginal lesions (Zinn).RDDRDD patients are treated with a variety of chemotherapy agents including cladribine, clofarabine, and the MAPK inhibitors (Simko 2014 Ped. Blood Cancer, Diamond 2019).JXGJXG patients may be observed when having only a modest number of skin lesions as they may spontaneously resolve. Patients with organ involvement or massive numbers of skin lesions respond to treatment with clofarabine and the MAPK inhibitors (Simko 2014 Ped. Blood Cancer, Diamond 2019.)ECDTreatment of ECD patients is now primarily with BRAF or MAPK inhibitors.(Haroche, Diamond 2018) Some patients are successfully treated with alpha interferon or anakinra (Arnaud, Cohen-Aubert).
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Therapies of Langerhans Cell Histiocytosis. LCHSingle bone lesions (not in the CNS risk group) are treated with surgery alone or with injection of steroids.CNS Risk bone lesions are treated with Velban and prednisone or cytarabine alone.Multifocal bone or multifocal low risk lesions are treated with Velban/prednisone or cytarabine alone (Gadner, Simko 2015).Multifocal High Risk lesions are treated with Velban/prednisone/6MP or cytarabine alone.If only skin lesions are present and not extensive, treatment may not be necessary. If treatment is needed, hydroxyurea alone or with methotrexate is very effective. (Zinn) Oral methotrexate or thalidomide are also used (McClain 2007). Topical ointments and PUVA are not very effective.Central nervous system involvement (pituitary or other mass lesions) is treated with cytarabine, cladribine, or MAPK inhibitors (McClain 2018).Neurodegenerative syndrome is treated with cytarabine or MAPK inhibitors (McClain 2018).If a patient does not respond to the standard therapy by the sixth week (or twelfth week for a partial response) they should be changed to the salvage therapy (Cytarabine, Cladribine, Cladribine/cytarabine, Clofarabine, or a MAPK inhibitor) (Simko 2015, Weitzman, Donadieu 2015, Simko 2014 Ped Blood Cancer, Eckstein).Adults should not be treated with Velban and prednisone because these drugs are not effective and cause excessive toxicity. Cytarabine has been shown to be a better therapy and cladribine has also been effective (Cantu). Oral hydroxyurea with or without oral methotrexate has been effective in treating skin and bone LCH, with special efficacy for vaginal lesions (Zinn).RDDRDD patients are treated with a variety of chemotherapy agents including cladribine, clofarabine, and the MAPK inhibitors (Simko 2014 Ped. Blood Cancer, Diamond 2019).JXGJXG patients may be observed when having only a modest number of skin lesions as they may spontaneously resolve. Patients with organ involvement or massive numbers of skin lesions respond to treatment with clofarabine and the MAPK inhibitors (Simko 2014 Ped. Blood Cancer, Diamond 2019.)ECDTreatment of ECD patients is now primarily with BRAF or MAPK inhibitors.(Haroche, Diamond 2018) Some patients are successfully treated with alpha interferon or anakinra (Arnaud, Cohen-Aubert).
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Overview of Large Granular Lymphocyte Leukemia
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SummaryLarge granular lymphocyte leukemia (LGLL) is a chronic blood disorder in which there is an increased number of large granular lymphocytes in the peripheral blood that accumulate over time. All cells in the body, including skin cells, liver cells and even immune cells, are meant to die off and be replaced by new cells throughout a person’s lifetime, but in patients with LGLL, large granular lymphocytes do not die off when they are supposed to. In general, LGLL is a disease that progresses very slowly, but these slow changes can lead to frequent infection, anemia and easy bleeding.IntroductionUsually, when someone has a viral infection like the flu, foreign antigens, such as viral proteins, are recognized by a specific type of white blood cell (usually a T-cell) and cause it to be activated to make many copies of itself (other T-cells) to battle the virus. These cells release toxic molecules to kill cells infected with the virus along with inflammatory signals called cytokines which tell the body that the virus has invaded. The body responds by prioritizing functions that fight the flu such as having the body make lymphocytes rather than other cell types like red blood cells, neutrophils or platelets. When these T-cells successfully fight off the virus, they die off to make room for other blood cells. Their death stops the release of the inflammatory signals, and the body goes back to its healthy, resting state. In people with LGL leukemia, these T-cells do not to die off, so the inflammatory signals keep being released, even when there is no longer a viral infection. The leukemic blood cells accumulate and there is less room for healthy cells. The leukemic cells also release inflammatory signals that tell the body to produce fewer red blood cells, platelets and neutrophils.LGL leukemia was first reported by Dr. Thomas Loughran in 1985 and described in the publication “Leukemia of Large Granular Lymphocytes: Association with Clonal Chromosomal Abnormalities and Autoimmune Neutropenia, Thrombocytopenia and Hemolytic Anemia” (Loughran et al, 1985). He described a disease characterized by neutropenia (low neutrophils), anemia (low red blood cells) and thrombocytopenia (low platelets). Neutrophils are cells that try to kill any foreign substances in the body before they can cause infection. Red blood cells transport oxygen to organs and tissues. Platelets cause blood to clot and stop bleeding when injury occurs. Patients with low neutrophils may experience recurrent infections. Patients with low red blood cells may experience shortness of breath and fatigue. Patients with low platelets may have trouble getting bleeding to stop when they are injured.
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Overview of Large Granular Lymphocyte Leukemia. SummaryLarge granular lymphocyte leukemia (LGLL) is a chronic blood disorder in which there is an increased number of large granular lymphocytes in the peripheral blood that accumulate over time. All cells in the body, including skin cells, liver cells and even immune cells, are meant to die off and be replaced by new cells throughout a person’s lifetime, but in patients with LGLL, large granular lymphocytes do not die off when they are supposed to. In general, LGLL is a disease that progresses very slowly, but these slow changes can lead to frequent infection, anemia and easy bleeding.IntroductionUsually, when someone has a viral infection like the flu, foreign antigens, such as viral proteins, are recognized by a specific type of white blood cell (usually a T-cell) and cause it to be activated to make many copies of itself (other T-cells) to battle the virus. These cells release toxic molecules to kill cells infected with the virus along with inflammatory signals called cytokines which tell the body that the virus has invaded. The body responds by prioritizing functions that fight the flu such as having the body make lymphocytes rather than other cell types like red blood cells, neutrophils or platelets. When these T-cells successfully fight off the virus, they die off to make room for other blood cells. Their death stops the release of the inflammatory signals, and the body goes back to its healthy, resting state. In people with LGL leukemia, these T-cells do not to die off, so the inflammatory signals keep being released, even when there is no longer a viral infection. The leukemic blood cells accumulate and there is less room for healthy cells. The leukemic cells also release inflammatory signals that tell the body to produce fewer red blood cells, platelets and neutrophils.LGL leukemia was first reported by Dr. Thomas Loughran in 1985 and described in the publication “Leukemia of Large Granular Lymphocytes: Association with Clonal Chromosomal Abnormalities and Autoimmune Neutropenia, Thrombocytopenia and Hemolytic Anemia” (Loughran et al, 1985). He described a disease characterized by neutropenia (low neutrophils), anemia (low red blood cells) and thrombocytopenia (low platelets). Neutrophils are cells that try to kill any foreign substances in the body before they can cause infection. Red blood cells transport oxygen to organs and tissues. Platelets cause blood to clot and stop bleeding when injury occurs. Patients with low neutrophils may experience recurrent infections. Patients with low red blood cells may experience shortness of breath and fatigue. Patients with low platelets may have trouble getting bleeding to stop when they are injured.
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Symptoms of Large Granular Lymphocyte Leukemia
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The symptoms that patients with LGL leukemia most commonly experience are related to the changes in neutrophils, red blood cells and platelets. Changes in neutrophils are the most common, followed by changes in red blood cells, with changes in platelets being the least common. Patients can also have a combination of these changes. Many patients with LGL leukemia report fatigue and flu-like symptoms or other symptoms that are commonly associated with having an active infection, even when they do not have an infection (Lamy & Loughran, 2003). As discussed above, the LGL cells that do not die off continue to make the same inflammatory signals that they would during an active infection, so these additional symptoms are likely due to the body continuing to respond to those signals. Patients with LGL leukemia have a higher-than-normal chance of having autoimmune diseases such as rheumatoid arthritis. Other autoimmune issues such as Sjogren syndrome, systemic lupus erythematosus and Hashimoto’s disease are also associated with LGL leukemia (Sokol & Loughran, 2006; Zhang et al. 2010). Swelling of the spleen and, rarely, the liver occurs in a small number of patients. Pure red cell aplasia has also been noted in a subset of patients.Studies have shown a life expectancy of 10 years after diagnosis (Shah et al, 2016). Although this data was accurate in the population at the time, it is not fully representative of current survival expectations. This information was collected on patients whose disease progression was quite advanced and who were generally older than the current average LGLL patient. It is now possible to diagnosis LGL leukemia earlier in the disease process, and a recent small scale study (Rivero et al. 2021) along with more extensive unpublished data from a patient Registry indicates that patients have an average and mean lifespan that is within a few years of the national average.
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Symptoms of Large Granular Lymphocyte Leukemia. The symptoms that patients with LGL leukemia most commonly experience are related to the changes in neutrophils, red blood cells and platelets. Changes in neutrophils are the most common, followed by changes in red blood cells, with changes in platelets being the least common. Patients can also have a combination of these changes. Many patients with LGL leukemia report fatigue and flu-like symptoms or other symptoms that are commonly associated with having an active infection, even when they do not have an infection (Lamy & Loughran, 2003). As discussed above, the LGL cells that do not die off continue to make the same inflammatory signals that they would during an active infection, so these additional symptoms are likely due to the body continuing to respond to those signals. Patients with LGL leukemia have a higher-than-normal chance of having autoimmune diseases such as rheumatoid arthritis. Other autoimmune issues such as Sjogren syndrome, systemic lupus erythematosus and Hashimoto’s disease are also associated with LGL leukemia (Sokol & Loughran, 2006; Zhang et al. 2010). Swelling of the spleen and, rarely, the liver occurs in a small number of patients. Pure red cell aplasia has also been noted in a subset of patients.Studies have shown a life expectancy of 10 years after diagnosis (Shah et al, 2016). Although this data was accurate in the population at the time, it is not fully representative of current survival expectations. This information was collected on patients whose disease progression was quite advanced and who were generally older than the current average LGLL patient. It is now possible to diagnosis LGL leukemia earlier in the disease process, and a recent small scale study (Rivero et al. 2021) along with more extensive unpublished data from a patient Registry indicates that patients have an average and mean lifespan that is within a few years of the national average.
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Causes of Large Granular Lymphocyte Leukemia
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The exact cause of LGL leukemia is not known. Ongoing research in the Loughran Lab at the University of Virginia has led researchers to theorize that patients develop LGLL following exposure to foreign antigens, potentially due to a viral infection. It is proposed that cells that are fighting off that virus are transformed by gene changes (mutations) and cannot die off as they typically would after they have fought off the virus (Kanchan & Loughran, 2003). These mutations develop in a group of mature cells after birth, so they are not passed down to a patient’s children. Recent research studies have catalogued the most frequently mutated genes in LGL leukemia (Olson et al., 2021; Cheon et al., 2022).
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Causes of Large Granular Lymphocyte Leukemia. The exact cause of LGL leukemia is not known. Ongoing research in the Loughran Lab at the University of Virginia has led researchers to theorize that patients develop LGLL following exposure to foreign antigens, potentially due to a viral infection. It is proposed that cells that are fighting off that virus are transformed by gene changes (mutations) and cannot die off as they typically would after they have fought off the virus (Kanchan & Loughran, 2003). These mutations develop in a group of mature cells after birth, so they are not passed down to a patient’s children. Recent research studies have catalogued the most frequently mutated genes in LGL leukemia (Olson et al., 2021; Cheon et al., 2022).
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Affects of Large Granular Lymphocyte Leukemia
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The incidence of LGL leukemia increases with age. It is usually diagnosed in older people and rarely occurs in individuals under 30 years old. LGLL almost never affects children and is very rare in patients under the age of twenty. In the United States, the incidence of LGLL is thought to be 0.2 to 0.72 cases out of every 1,000,000 people, but this may be an underestimate. Patients in an early stage of the disease or people without symptoms may go undiagnosed.
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Affects of Large Granular Lymphocyte Leukemia. The incidence of LGL leukemia increases with age. It is usually diagnosed in older people and rarely occurs in individuals under 30 years old. LGLL almost never affects children and is very rare in patients under the age of twenty. In the United States, the incidence of LGLL is thought to be 0.2 to 0.72 cases out of every 1,000,000 people, but this may be an underestimate. Patients in an early stage of the disease or people without symptoms may go undiagnosed.
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Related disorders of Large Granular Lymphocyte Leukemia
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Related disorders of Large Granular Lymphocyte Leukemia.
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Diagnosis of Large Granular Lymphocyte Leukemia
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LGL leukemia cells can develop from two different types of large granular lymphocytes, cytotoxic T-cells and natural killer (NK) cells. The type associated with NK cells is very rare, and accounts for only 10-15% of cases. LGL leukemia of either type typically exhibits a slow-moving, chronic disease course. However there is an aggressive form of NK type of LGL leukemia that is primarily seen in Asian populations and is distinctly different than the chronic type of NK-LGL leukemia. Therefore, it is important to have an accurate and thorough workup focused on the known markers for LGL leukemia to correctly categorize the type of LGL leukemia.LGLL is usually discovered when an abnormally high white blood cell count and/or lower numbers of red blood cells, platelets or neutrophils are noticed in routine blood work. LGLs have a very distinctive cellular morphology and can be detected by visual examination of a blood smear on a microscope slide. A definitive diagnosis is established when there is an increased number of LGL in the blood which are clonally expanded. The combination of the following tests are required:1. Complete blood cell count: This test will measure the number of various types of blood cells including white blood cells, red blood cells and platelets. A high number of lymphocytes and/or a low number of red blood cells, platelets or neutrophils can be indicators of LGL leukemia.2. Flow cytometry: In this test blood cells are examined with antibodies to determine if there are more large granular lymphocytes in the blood than in a healthy individual. This test helps establish the diagnosis of LGL leukemia, differentiates between T and NK LGL leukemia and rules out other disorders.3. T-cell gene rearrangement: This genetic test is used to show clonality, meaning that there is a group of cells with the same T-cell receptor, which indicates that they all came from the same parent cell.Additional TestingBone marrow biopsy: This test is conducted by removing a sample of bone marrow and evaluating it to determine whether abnormal cells are present. This is usually not required to make a diagnosis of LGLL, since the testing above can be done on the blood. However, it is often done early in the diagnostic process to ensure that a more acute or potentially fatal illness, such as myelodysplastic syndrome (MDS) is not missed while evaluating the patient for LGLL.
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Diagnosis of Large Granular Lymphocyte Leukemia. LGL leukemia cells can develop from two different types of large granular lymphocytes, cytotoxic T-cells and natural killer (NK) cells. The type associated with NK cells is very rare, and accounts for only 10-15% of cases. LGL leukemia of either type typically exhibits a slow-moving, chronic disease course. However there is an aggressive form of NK type of LGL leukemia that is primarily seen in Asian populations and is distinctly different than the chronic type of NK-LGL leukemia. Therefore, it is important to have an accurate and thorough workup focused on the known markers for LGL leukemia to correctly categorize the type of LGL leukemia.LGLL is usually discovered when an abnormally high white blood cell count and/or lower numbers of red blood cells, platelets or neutrophils are noticed in routine blood work. LGLs have a very distinctive cellular morphology and can be detected by visual examination of a blood smear on a microscope slide. A definitive diagnosis is established when there is an increased number of LGL in the blood which are clonally expanded. The combination of the following tests are required:1. Complete blood cell count: This test will measure the number of various types of blood cells including white blood cells, red blood cells and platelets. A high number of lymphocytes and/or a low number of red blood cells, platelets or neutrophils can be indicators of LGL leukemia.2. Flow cytometry: In this test blood cells are examined with antibodies to determine if there are more large granular lymphocytes in the blood than in a healthy individual. This test helps establish the diagnosis of LGL leukemia, differentiates between T and NK LGL leukemia and rules out other disorders.3. T-cell gene rearrangement: This genetic test is used to show clonality, meaning that there is a group of cells with the same T-cell receptor, which indicates that they all came from the same parent cell.Additional TestingBone marrow biopsy: This test is conducted by removing a sample of bone marrow and evaluating it to determine whether abnormal cells are present. This is usually not required to make a diagnosis of LGLL, since the testing above can be done on the blood. However, it is often done early in the diagnostic process to ensure that a more acute or potentially fatal illness, such as myelodysplastic syndrome (MDS) is not missed while evaluating the patient for LGLL.
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Therapies of Large Granular Lymphocyte Leukemia
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TreatmentMany patients who are newly diagnosed with LGL leukemia will not need treatment for some time after diagnosis. These patients enter what is referred to as the “watch and wait” phase of their disease management. Physical exams and regular blood tests to look for falling numbers of red blood cells, platelets and neutrophils along with the onset of new symptoms related to LGLL may be all that is needed. A decline in blood counts below a certain level or onset of symptoms that continuously affect physical functioning are metrics that determine the need for treatment. About 5-10% of LGLL patients never need treatment in their lifetime. The need for treatment is still based primarily on worsening blood counts or symptoms especially related to reduced neutrophil or red blood cell counts, not on the number of leukemic cells. Treatment is generally recommended when absolute neutrophil count (ANC) drops below 0.5 cellsx10E9/L (500 cellsx10E6/L at some labs) or recurrent infections start to occur, when hemoglobin drops below 8.0 g/dL or a patient needs frequent blood transfusions, or when platelet count drops below 20 cellsx10E9/L. Patients with LGL leukemia-associated autoimmune disease, like rheumatoid arthritis, may be treated with medications to manage both the autoimmune disease symptoms and kill the LGLL cells. Patients with severe symptoms who do not fall into the lower blood count ranges may begin treatment before numbers fall into the at-risk range as well. The decision to start treatment is complex and should be made under the close supervision of a patient’s treating physician. The treating physician will also need to monitor a patient’s blood numbers more closely during treatment to evaluate whether the treatment is safe and, later, whether it is working. The medications used to treat LGL leukemia are called Immunosuppressives. They are used to decrease the survival of immune cells like lymphocytes. Treatment usually takes 4-6 months to show a stable improvement of low blood counts. The three immunosuppressives that are used in LGL leukemia are methotrexate, cyclosporine A and cyclophosphamide. They are all manufactured under several brand names, so care should be taken to check that recommended treatments fall into these three categories. When they are given in very high doses, methotrexate and cyclophosphamide are used as chemotherapeutic drugs, but they are used in much lower doses to act as immunosuppressives in LGL leukemia. Therefore, when used to treat LGLL they do not have the same side effects as they do as chemotherapeutics. It is important to note that online information about these agents generally only covers the side effects that are associated with chemotherapy. Although each medication can only be expected to work in 40-60% of patients individually (depending on the drug), about 90% of patients will respond to one of these three medications. For the remaining 10% of patients, several alternative therapies are available, but because they have been less well studied in the LGLL patient population, they are recommended on a case-by-case basis (Loughran and Lamy, 2011). In addition to the therapies that help LGLL cells die off, there are supportive therapies that can help patients with LGLL. These therapeutics can help keep patients healthy so they need active treatment less infrequently and can keep their other blood cell numbers stable during treatment. These supportive medications include steroids, like prednisone, to help support the bone marrow in making normal cells, colony stimulating factors to support neutrophil numbers and transfusions to help increase red blood cell or platelet counts. There is also clinical and research data to support the use of supplements in LGLL patients. Vitamin D has been shown to have supportive effects in managing the effects of LGL leukemia and folate is also a common supportive agent, especially when patients are taking the immunosuppressive drug methotrexate.
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Therapies of Large Granular Lymphocyte Leukemia. TreatmentMany patients who are newly diagnosed with LGL leukemia will not need treatment for some time after diagnosis. These patients enter what is referred to as the “watch and wait” phase of their disease management. Physical exams and regular blood tests to look for falling numbers of red blood cells, platelets and neutrophils along with the onset of new symptoms related to LGLL may be all that is needed. A decline in blood counts below a certain level or onset of symptoms that continuously affect physical functioning are metrics that determine the need for treatment. About 5-10% of LGLL patients never need treatment in their lifetime. The need for treatment is still based primarily on worsening blood counts or symptoms especially related to reduced neutrophil or red blood cell counts, not on the number of leukemic cells. Treatment is generally recommended when absolute neutrophil count (ANC) drops below 0.5 cellsx10E9/L (500 cellsx10E6/L at some labs) or recurrent infections start to occur, when hemoglobin drops below 8.0 g/dL or a patient needs frequent blood transfusions, or when platelet count drops below 20 cellsx10E9/L. Patients with LGL leukemia-associated autoimmune disease, like rheumatoid arthritis, may be treated with medications to manage both the autoimmune disease symptoms and kill the LGLL cells. Patients with severe symptoms who do not fall into the lower blood count ranges may begin treatment before numbers fall into the at-risk range as well. The decision to start treatment is complex and should be made under the close supervision of a patient’s treating physician. The treating physician will also need to monitor a patient’s blood numbers more closely during treatment to evaluate whether the treatment is safe and, later, whether it is working. The medications used to treat LGL leukemia are called Immunosuppressives. They are used to decrease the survival of immune cells like lymphocytes. Treatment usually takes 4-6 months to show a stable improvement of low blood counts. The three immunosuppressives that are used in LGL leukemia are methotrexate, cyclosporine A and cyclophosphamide. They are all manufactured under several brand names, so care should be taken to check that recommended treatments fall into these three categories. When they are given in very high doses, methotrexate and cyclophosphamide are used as chemotherapeutic drugs, but they are used in much lower doses to act as immunosuppressives in LGL leukemia. Therefore, when used to treat LGLL they do not have the same side effects as they do as chemotherapeutics. It is important to note that online information about these agents generally only covers the side effects that are associated with chemotherapy. Although each medication can only be expected to work in 40-60% of patients individually (depending on the drug), about 90% of patients will respond to one of these three medications. For the remaining 10% of patients, several alternative therapies are available, but because they have been less well studied in the LGLL patient population, they are recommended on a case-by-case basis (Loughran and Lamy, 2011). In addition to the therapies that help LGLL cells die off, there are supportive therapies that can help patients with LGLL. These therapeutics can help keep patients healthy so they need active treatment less infrequently and can keep their other blood cell numbers stable during treatment. These supportive medications include steroids, like prednisone, to help support the bone marrow in making normal cells, colony stimulating factors to support neutrophil numbers and transfusions to help increase red blood cell or platelet counts. There is also clinical and research data to support the use of supplements in LGLL patients. Vitamin D has been shown to have supportive effects in managing the effects of LGL leukemia and folate is also a common supportive agent, especially when patients are taking the immunosuppressive drug methotrexate.
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Large Granular Lymphocyte Leukemia
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nord_697_0
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Overview of Larsen Syndrome
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SummaryLarsen syndrome is a rare genetic disorder that has been associated with a wide variety of different symptoms. Characteristic findings of the disorder include dislocations of the large joints, skeletal malformations, and distinctive facial and limb features. Additional findings may include abnormal curvature of the spine, clubfoot, short stature, and breathing (respiratory) difficulties. The classic form of Larsen syndrome is caused by mutations of the FLNB gene with a frequency of 1 in 100,000. The mutation may occur spontaneously or be inherited as an autosomal dominant trait. Introduction FLNB-related disorders are a group of disorders (including autosomal dominant Larsen syndrome) that occur due to mutations of the Filamin B gene (FLNB) gene. This group includes atelosteogenesis types I and III, boomerang dysplasia and spondylocarpotarsal syndrome. These disorders are characterized by skeletal abnormalities affecting the bones of the hands and feet, the bones of the spine (vertebrae), joint dislocations, and distinctive facial features. The specific symptoms and severity of these disorders may vary greatly even among members of the same family. Researchers have identified individuals with multiple joint dislocations and skeletal anomalies whose condition appears to be inherited as an autosomal recessive trait. These individuals often have different radiological findings than those with classic Larsen syndrome. Mutations in the carbohydrate sulfotransferase 3 (CHST3) gene have been identified in patients with so-called autosomal recessive Larsen syndrome that also includes humero-spinal dysostosis and spondyloepiphyseal dysplasia Omani type. A variant of Larsen syndrome was reported in patients from Reunion Island in the southern Indian Ocean and characterized by dwarfism, hyperlaxity, multiple dislocations and distinctive facial features. It is inherited in an autosomal recessive fashion and results from a founder homozygous missense mutation in B4GALT7. Mutations in the linkeropathy genes (XYLT1, XYLT2, B4GALT7, B3GALT6, and B3GAT3) can be associated with ocular findings, including blue sclerae, refractive errors, corneal clouding, strabismus, nystagmus, cataracts, glaucoma, and retinal abnormalities, including retinal detachment. A consanguineous Saudi family with severe and recurrent large joint dislocation and severe myopia, was identified with a homozygous truncating variant in GZF1. These ocular findings are not seen in FLNB-related disorders. Since these disorders are known to be caused by different genes than classic, autosomal dominant Larsen syndrome, the term autosomal recessive Larsen syndrome should probably be avoided to prevent confusion with clinical disorders resulting from mutations in FLNB.
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Overview of Larsen Syndrome. SummaryLarsen syndrome is a rare genetic disorder that has been associated with a wide variety of different symptoms. Characteristic findings of the disorder include dislocations of the large joints, skeletal malformations, and distinctive facial and limb features. Additional findings may include abnormal curvature of the spine, clubfoot, short stature, and breathing (respiratory) difficulties. The classic form of Larsen syndrome is caused by mutations of the FLNB gene with a frequency of 1 in 100,000. The mutation may occur spontaneously or be inherited as an autosomal dominant trait. Introduction FLNB-related disorders are a group of disorders (including autosomal dominant Larsen syndrome) that occur due to mutations of the Filamin B gene (FLNB) gene. This group includes atelosteogenesis types I and III, boomerang dysplasia and spondylocarpotarsal syndrome. These disorders are characterized by skeletal abnormalities affecting the bones of the hands and feet, the bones of the spine (vertebrae), joint dislocations, and distinctive facial features. The specific symptoms and severity of these disorders may vary greatly even among members of the same family. Researchers have identified individuals with multiple joint dislocations and skeletal anomalies whose condition appears to be inherited as an autosomal recessive trait. These individuals often have different radiological findings than those with classic Larsen syndrome. Mutations in the carbohydrate sulfotransferase 3 (CHST3) gene have been identified in patients with so-called autosomal recessive Larsen syndrome that also includes humero-spinal dysostosis and spondyloepiphyseal dysplasia Omani type. A variant of Larsen syndrome was reported in patients from Reunion Island in the southern Indian Ocean and characterized by dwarfism, hyperlaxity, multiple dislocations and distinctive facial features. It is inherited in an autosomal recessive fashion and results from a founder homozygous missense mutation in B4GALT7. Mutations in the linkeropathy genes (XYLT1, XYLT2, B4GALT7, B3GALT6, and B3GAT3) can be associated with ocular findings, including blue sclerae, refractive errors, corneal clouding, strabismus, nystagmus, cataracts, glaucoma, and retinal abnormalities, including retinal detachment. A consanguineous Saudi family with severe and recurrent large joint dislocation and severe myopia, was identified with a homozygous truncating variant in GZF1. These ocular findings are not seen in FLNB-related disorders. Since these disorders are known to be caused by different genes than classic, autosomal dominant Larsen syndrome, the term autosomal recessive Larsen syndrome should probably be avoided to prevent confusion with clinical disorders resulting from mutations in FLNB.
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Larsen Syndrome
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nord_697_1
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Symptoms of Larsen Syndrome
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The symptoms and severity of Larsen syndrome vary greatly, including between individuals belonging to the same family. In one large family whose members had Larsen syndrome caused by one of the recurring mutations, some affected individuals have cleft palate and multiple large joint dislocations, but others have no major anomalies and manifested only short stature and mild features, such as short distal phalanges (toe and fingertip bones) and extra bones in the wrist and ankle Mild short stature is common with height below the tenth percentile in 70% of the cases.Skeletal and joint abnormalities with distinctive facial features are the most common findings associated with the classic, autosomal dominant Larsen syndrome. Some symptoms associated with Larsen syndrome are present at birth, such as dislocation of large joints (80% hip, 80% knee, and 65% elbow) with subluxation of the shoulders the only large joint manifestation in one mildly affected person. Clubfoot is present in about 75% of affected individuals. In addition, the joints of individuals with Larsen syndrome may be extremely lax or loose (hypermobility), which may make them more prone to dislocation. The fingers, especially the thumbs, may be short and broad with squared or rounded tips. Extra bones may be present in the wrists and ankles (supernumerary carpal and tarsal bones), and some of these bones may fuse together during childhood. Retrognathia, patellar dislocation, kyphoscoliosis and dural ectasia also occurs.Spine abnormalities occur in 84% of individuals with Larsen syndrome including abnormal sideways curvature of the spine (scoliosis) or front-to-back curvature of the spinal bones (vertebrae) in the neck (cervical kyphosis). Cervical kyphosis occurs in 50% of affected individuals, usually from subluxation or fusion of the cervical vertebral bodies, which is usually associated with posterior vertebral arch dysraphism (i.e., dysplasia of the vertebral laminae and hypoplasia of the lateral processes of all cervical vertebrae). Individuals with Larsen syndrome and cervical spine dysplasia are at significant risk for cervical cord damage and secondary paralysis, which occurs in at least 15% of patients.Individuals with Larsen also have distinctive facial features, which include eyes that are wider apart than normal (hypertelorism), prominent forehead, and depressed bridge of the nose. The middle portion of the face may appear flattened. Incomplete closure of the roof of the mouth (cleft palate) or a cleft in the soft tissue that hangs down in the back of the throat (bifid uvula) may also occur in 15% of affected individuals. Deafness is common, usually preceded by ringing in the ears (tinnitus), and conductive deafness may be associated with malformations of the middle ear ossicles in 21% of individuals.A few individuals with classic Larsen syndrome have developed abnormal softening of the cartilage of the windpipe (trachea), a condition known as tracheomalacia, but more severe conditions associated with FLNB mutations, such as atelosteogenesis, can have severe laryngotrachiomalacia.Many individuals have been described in the medical literature with a more severe form of Larsen syndrome. Such individuals have developed additional findings to those discussed above including learning disabilities, developmental delay, life-threatening respiratory (breathing) abnormalities, and heart defects. These conditions are now known to result from different mutations in the FLNB gene and are discussed further in the Related Disorders section of this report.
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Symptoms of Larsen Syndrome. The symptoms and severity of Larsen syndrome vary greatly, including between individuals belonging to the same family. In one large family whose members had Larsen syndrome caused by one of the recurring mutations, some affected individuals have cleft palate and multiple large joint dislocations, but others have no major anomalies and manifested only short stature and mild features, such as short distal phalanges (toe and fingertip bones) and extra bones in the wrist and ankle Mild short stature is common with height below the tenth percentile in 70% of the cases.Skeletal and joint abnormalities with distinctive facial features are the most common findings associated with the classic, autosomal dominant Larsen syndrome. Some symptoms associated with Larsen syndrome are present at birth, such as dislocation of large joints (80% hip, 80% knee, and 65% elbow) with subluxation of the shoulders the only large joint manifestation in one mildly affected person. Clubfoot is present in about 75% of affected individuals. In addition, the joints of individuals with Larsen syndrome may be extremely lax or loose (hypermobility), which may make them more prone to dislocation. The fingers, especially the thumbs, may be short and broad with squared or rounded tips. Extra bones may be present in the wrists and ankles (supernumerary carpal and tarsal bones), and some of these bones may fuse together during childhood. Retrognathia, patellar dislocation, kyphoscoliosis and dural ectasia also occurs.Spine abnormalities occur in 84% of individuals with Larsen syndrome including abnormal sideways curvature of the spine (scoliosis) or front-to-back curvature of the spinal bones (vertebrae) in the neck (cervical kyphosis). Cervical kyphosis occurs in 50% of affected individuals, usually from subluxation or fusion of the cervical vertebral bodies, which is usually associated with posterior vertebral arch dysraphism (i.e., dysplasia of the vertebral laminae and hypoplasia of the lateral processes of all cervical vertebrae). Individuals with Larsen syndrome and cervical spine dysplasia are at significant risk for cervical cord damage and secondary paralysis, which occurs in at least 15% of patients.Individuals with Larsen also have distinctive facial features, which include eyes that are wider apart than normal (hypertelorism), prominent forehead, and depressed bridge of the nose. The middle portion of the face may appear flattened. Incomplete closure of the roof of the mouth (cleft palate) or a cleft in the soft tissue that hangs down in the back of the throat (bifid uvula) may also occur in 15% of affected individuals. Deafness is common, usually preceded by ringing in the ears (tinnitus), and conductive deafness may be associated with malformations of the middle ear ossicles in 21% of individuals.A few individuals with classic Larsen syndrome have developed abnormal softening of the cartilage of the windpipe (trachea), a condition known as tracheomalacia, but more severe conditions associated with FLNB mutations, such as atelosteogenesis, can have severe laryngotrachiomalacia.Many individuals have been described in the medical literature with a more severe form of Larsen syndrome. Such individuals have developed additional findings to those discussed above including learning disabilities, developmental delay, life-threatening respiratory (breathing) abnormalities, and heart defects. These conditions are now known to result from different mutations in the FLNB gene and are discussed further in the Related Disorders section of this report.
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Larsen Syndrome
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Causes of Larsen Syndrome
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The classic form of Larsen syndrome follows autosomal dominant inheritance. 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 percent for each pregnancy regardless of the sex of the resulting child.Investigators have determined that classic Larsen syndrome results from mutations in the Filamin B (FLNB) gene located on the short arm of chromosome 3 (3p14). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomal locations are further specified by the dark and light bands along each arm. For example, “chromosome 3p14” refers to band 14 on the short arm of chromosome 3. These numbered bands specify the location of the genes that are located in this region of the chromosome.The FLNB gene contains instructions for creating (encoding) a protein known as Filamin B, which plays a role in the proper development of the inner framework of a cell (cytoskeleton). Mutations in FLNB result in dysfunction of the protein encoded by this gene. Filamin B (FLNB) is a large dimeric actin-binding protein which crosslinks actin cytoskeleton filaments into a dynamic structure. Some researchers suggest that certain cases believed to be recessively inherited cases of Larsen syndrome may represent germline mosaicism. In germline mosaicism, some of a parent’s reproductive cells (germ cells) carry the FLNB gene mutation, while other germ cells contain normal FLNB genes (“mosaicism”). The other cells in the parent’s body do not have the mutation, so these parents are unaffected. As a result, one or more of the parent’s children may inherit the germ cell gene FLNB mutation, leading to the development of Larsen syndrome, while the parent does not appear to have this disorder (asymptomatic carrier). Germline mosaicism may be suspected when apparently unaffected parents have more than one child with the same autosomal dominant genetic condition. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that have the mutation versus the percentage that do not. There is no test for germline mutation prior to pregnancy. Testing during a pregnancy may be available and is best discussed directly with a genetic specialist.Researchers have determined that a few cases of Larsen syndrome may result from somatic mosaicism. In somatic mosaicism, the mutation of the FLNB gene causing Larsen syndrome occurs after fertilization and is not inherited. The mutation is found in some of the cells of the body, but not in others. The severity of the disease in these cases depends on the percentage of cells affected, and it is less severe than in individuals who have the mutation in all of their cells. In the past, such cases were thought to result from autosomal recessive inheritance when a parent’s features were too mild to be recognized as Larsen syndrome.Spondylocarpotarsal (SCT) syndrome is caused by mutations in FLNB that result in absent filament B protein. The mutations associated with Larsen syndrome and atelosteogenesis types I and III (AOI and AOIII) encode a full-length filamin B protein that does not function properly. In some instances, the same mutation has caused both AOI and AOIII. Somatic FLNB mosaicism can complicate the presentation of these conditions.
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Causes of Larsen Syndrome. The classic form of Larsen syndrome follows autosomal dominant inheritance. 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 percent for each pregnancy regardless of the sex of the resulting child.Investigators have determined that classic Larsen syndrome results from mutations in the Filamin B (FLNB) gene located on the short arm of chromosome 3 (3p14). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomal locations are further specified by the dark and light bands along each arm. For example, “chromosome 3p14” refers to band 14 on the short arm of chromosome 3. These numbered bands specify the location of the genes that are located in this region of the chromosome.The FLNB gene contains instructions for creating (encoding) a protein known as Filamin B, which plays a role in the proper development of the inner framework of a cell (cytoskeleton). Mutations in FLNB result in dysfunction of the protein encoded by this gene. Filamin B (FLNB) is a large dimeric actin-binding protein which crosslinks actin cytoskeleton filaments into a dynamic structure. Some researchers suggest that certain cases believed to be recessively inherited cases of Larsen syndrome may represent germline mosaicism. In germline mosaicism, some of a parent’s reproductive cells (germ cells) carry the FLNB gene mutation, while other germ cells contain normal FLNB genes (“mosaicism”). The other cells in the parent’s body do not have the mutation, so these parents are unaffected. As a result, one or more of the parent’s children may inherit the germ cell gene FLNB mutation, leading to the development of Larsen syndrome, while the parent does not appear to have this disorder (asymptomatic carrier). Germline mosaicism may be suspected when apparently unaffected parents have more than one child with the same autosomal dominant genetic condition. The likelihood of a parent passing on a mosaic germline mutation to a child depends upon the percentage of the parent’s germ cells that have the mutation versus the percentage that do not. There is no test for germline mutation prior to pregnancy. Testing during a pregnancy may be available and is best discussed directly with a genetic specialist.Researchers have determined that a few cases of Larsen syndrome may result from somatic mosaicism. In somatic mosaicism, the mutation of the FLNB gene causing Larsen syndrome occurs after fertilization and is not inherited. The mutation is found in some of the cells of the body, but not in others. The severity of the disease in these cases depends on the percentage of cells affected, and it is less severe than in individuals who have the mutation in all of their cells. In the past, such cases were thought to result from autosomal recessive inheritance when a parent’s features were too mild to be recognized as Larsen syndrome.Spondylocarpotarsal (SCT) syndrome is caused by mutations in FLNB that result in absent filament B protein. The mutations associated with Larsen syndrome and atelosteogenesis types I and III (AOI and AOIII) encode a full-length filamin B protein that does not function properly. In some instances, the same mutation has caused both AOI and AOIII. Somatic FLNB mosaicism can complicate the presentation of these conditions.
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Larsen Syndrome
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nord_697_3
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Affects of Larsen Syndrome
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Larsen syndrome affects males and females in equal numbers. It is estimated to occur in 1 in 100,000 individuals in the general population. Because of the difficulty in diagnosing Larsen syndrome, determining its true frequency in the general population is difficult. Larsen syndrome was first described in the medical literature as a distinct disease entity by Dr. Loren Larsen in 1950.An autosomal recessive form of “Larsen syndrome” was identified in several large families on Reunion Island in the Indian Ocean off the east coast of Africa. This disorder results in multiple joint dislocations, but it has different clinical and radiologic features, and it is caused by a founder homozygous missense mutation in B4GALT7. Mutations in the carbohydrate sulfotransferase 3 (CHST3) gene have been identified in patients with so-called autosomal recessive Larsen syndrome. Homozygous truncating GZF1 variants have also been reported in consanguineous Saudi families affected by severe myopia, retinal detachment, and recurrent large joint dislocations.
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Affects of Larsen Syndrome. Larsen syndrome affects males and females in equal numbers. It is estimated to occur in 1 in 100,000 individuals in the general population. Because of the difficulty in diagnosing Larsen syndrome, determining its true frequency in the general population is difficult. Larsen syndrome was first described in the medical literature as a distinct disease entity by Dr. Loren Larsen in 1950.An autosomal recessive form of “Larsen syndrome” was identified in several large families on Reunion Island in the Indian Ocean off the east coast of Africa. This disorder results in multiple joint dislocations, but it has different clinical and radiologic features, and it is caused by a founder homozygous missense mutation in B4GALT7. Mutations in the carbohydrate sulfotransferase 3 (CHST3) gene have been identified in patients with so-called autosomal recessive Larsen syndrome. Homozygous truncating GZF1 variants have also been reported in consanguineous Saudi families affected by severe myopia, retinal detachment, and recurrent large joint dislocations.
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Larsen Syndrome
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nord_697_4
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Related disorders of Larsen Syndrome
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Symptoms of the following disorders can be similar to those of Larsen syndrome. Comparisons may be useful for a differential diagnosis. For more information on these disorders, use the specific disorder name as a search term in the Rare Disease Database.Atelosteogenesis type I (AOI) and atelosteogenesis type III (AOIII) were once thought to be different conditions, but now they are thought to represent a spectrum of more severe, but similar disorders resulting from FLNB mutations. AOIII is milder than AOI, commonly with survival beyond the neonatal period. Clinical findings include dislocated hips, knees, and elbows and clubfeet. Radiographic features include distal tapering of the humeri and femora, short and broad tubular bones of the hands and feet, and mild vertebral hypoplasia. Infants with AOIII can survive the neonatal period but may require intensive and invasive support to do so. They have significant problems with respiratory insufficiency as a result of laryngotracheomalacia and thoracic hypoplasia. Infants with AOIII have been born to parents with milder phenotypes (similar to Larsen syndrome). Such parents have been found to have milder features due to somatic mosaicism, while their offspring have a severe phenotype due to a non-mosaic germline mutation.AOI results in perinatal lethality with severe short-limbed dwarfism, dislocated hips, knees, and elbows, and clubfeet. Radiographic features include marked vertebral flattening; hypoplastic pelvis; incomplete or absent, shortened, or distally-tapered humeri and femora; absent, shortened, or bowed radii; shortened and bowed ulnae and tibiae; absent fibulae; and incompletely ossified metacarpals and phalanges.Boomerang dysplasia is a perinatal lethal bone dysplasia with close similarities to AOI, distinguished primarily by characteristic bowing of the femora and, occasionally, extraskeletal manifestations including encephalocele and omphalocele. On prenatal ultrasound examination, the findings of boomerang dysplasia and AOI consist of thoracic hypoplasia and limb shortening with delayed or absent ossification of vertebral and appendicular elements. Joint dislocations may be evident. Definitive diagnosis by ultrasound examination alone is seldom possible. Polyhydramnios can complicate the pregnancy, and neonates with boomerang dysplasia or AOI die shortly after birth from cardiorespiratory insufficiency.Spondylocarpotarsal syndrome (SCT) syndrome is an autosomal recessive condition resulting from FLNB mutations. It is characterized by disproportionate short stature, with vertebral anomalies consisting of block vertebrae, scoliosis, lordosis, carpal and tarsal fusions, joint laxity, clubfeet or flat feet, and mild facial features consisting of round face, frontal bossing, short up-turned nose, cleft palate, conductive hearing loss, and dental enamel hypoplasia. SCT syndrome has also been associated with retinal anomalies and sensorineural deafness. The cataracts and retinal abnormalities described in one family with SCT syndrome were not severe enough to impair vision. Intelligence is normal.Researchers have also identified individuals with multiple joint dislocations and skeletal anomalies whose condition appears to be inherited as an autosomal recessive trait. These individuals often have different radiological findings than those with classic Larsen syndrome. Deficiency of carbohydrate sulfotransferase 3 (CHST3 or also called chondroitin-6-sulfotransferase) has been diagnosed in patients with so-called autosomal recessive Larsen syndrome, humero-spinal dysostosis and spondyloepiphyseal dysplasia Omani type. This condition is now called spondyloepiphyseal dysplasia with dislocations. Key clinical features include congenital dislocation of the knees, elbow joint dysplasia with subluxation and limited extension, hip dysplasia or dislocation, clubfeet, short stature, and kyphoscoliosis developing in late childhood. Analysis of chondroitin sulfate proteoglycans in dermal fibroblasts showed markedly decreased 6-O-sulfation with enhanced 4-O-sulfation, confirming functional impairment of CHST3, and distinguishing these fibroblasts from diastrophic dysplasia sulphate transporter (DTDST)-deficient cells.Larsen of Reunion Island syndrome has clinical manifestations which include dislocations of large joints with ligamentous hyperlaxity, short stature and characteristic facial features (round flat face, prominent forehead, prominent eyes with under-eye shawdows, and small mouth). Radiological features include dislocations of knees, hips, elbows and fingers, advanced carpal ossification, widened metaphyses, particularly at the knees, and radio-ulnar synostosis. Larsen of Reunion Island syndrome is caused by a founder homozygous missense mutation in B4GALT7. Joint hypermobility is present in all patients reported with B4GALT7 mutations, but joint dislocations have only been reported in the patients from Reunion Island. These clinical differences might be explained by different functional consequences of the reported mutations with variable quantitative effect on glycosaminoglycan biosynthesis. B4GALT7 is directly involved in the biosynthesis of proteoglycans.Desbuquois syndrome is a rare genetic disorder characterized by loose or lax joints, distinctive facial features, and short stature with abnormally short arms and legs. Affected individuals may have distinctive facial features including prominent eyes, a small jaw (micrognathia), and a rounded, flattened face. Abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) may also develop. Some individuals have skeletal abnormalities affecting the hands. Desbuquois syndrome is inherited as an autosomal recessive condition due to mutations in calcium-activated nucleotidase 1 (CANT1).Thus, there are four different disorders in the multiple dislocation group, autosomal dominant Larsen syndrome (FLNB), and three autosomal recessive disorders: spondyloepiphyseal dysplasia with dislocations (CHST3), Larsen of Reunion Island (B4GALT7) and Desbuquois dysplasia (CANT1). These latter disorders differ from classic Larsen syndrome and the term autosomal recessive Larsen syndrome should probably be avoided to prevent confusion with clinical disorders resulting from mutations in FLNB.FLNA-related disorders are a group of disorders that occur due to mutations of the filamin A (FLNA) gene. This group includes oto-palato-digita (OPD) syndromes types I and II, frontometaphyseal dysplasia (FMD), and Melnick-Needles syndrome. These disorders are characterized by varying degrees of skeletal malformation (dysplasia). Affected individuals may develop mild symptoms as seen with OPD type I or more severe symptoms as may be associated with FMD or OPD II.Ehlers-Danlos syndrome is a group of hereditary connective tissue disorders. Associated features may vary greatly, depending on the specific form of the disorder present and other factors. However, primary findings may include abnormally flexible, loose joints (articular hypermobility) that may easily become dislocated; unusually loose, thin, “stretchy” skin; and excessive fragility of the skin, blood vessels, and other bodily tissues and membranes.Additional disorders may be characterized by distinctive facial features, multiple dislocations, additional skeletal abnormalities, and/or other findings similar to those associated with Larsen syndrome.
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Related disorders of Larsen Syndrome. Symptoms of the following disorders can be similar to those of Larsen syndrome. Comparisons may be useful for a differential diagnosis. For more information on these disorders, use the specific disorder name as a search term in the Rare Disease Database.Atelosteogenesis type I (AOI) and atelosteogenesis type III (AOIII) were once thought to be different conditions, but now they are thought to represent a spectrum of more severe, but similar disorders resulting from FLNB mutations. AOIII is milder than AOI, commonly with survival beyond the neonatal period. Clinical findings include dislocated hips, knees, and elbows and clubfeet. Radiographic features include distal tapering of the humeri and femora, short and broad tubular bones of the hands and feet, and mild vertebral hypoplasia. Infants with AOIII can survive the neonatal period but may require intensive and invasive support to do so. They have significant problems with respiratory insufficiency as a result of laryngotracheomalacia and thoracic hypoplasia. Infants with AOIII have been born to parents with milder phenotypes (similar to Larsen syndrome). Such parents have been found to have milder features due to somatic mosaicism, while their offspring have a severe phenotype due to a non-mosaic germline mutation.AOI results in perinatal lethality with severe short-limbed dwarfism, dislocated hips, knees, and elbows, and clubfeet. Radiographic features include marked vertebral flattening; hypoplastic pelvis; incomplete or absent, shortened, or distally-tapered humeri and femora; absent, shortened, or bowed radii; shortened and bowed ulnae and tibiae; absent fibulae; and incompletely ossified metacarpals and phalanges.Boomerang dysplasia is a perinatal lethal bone dysplasia with close similarities to AOI, distinguished primarily by characteristic bowing of the femora and, occasionally, extraskeletal manifestations including encephalocele and omphalocele. On prenatal ultrasound examination, the findings of boomerang dysplasia and AOI consist of thoracic hypoplasia and limb shortening with delayed or absent ossification of vertebral and appendicular elements. Joint dislocations may be evident. Definitive diagnosis by ultrasound examination alone is seldom possible. Polyhydramnios can complicate the pregnancy, and neonates with boomerang dysplasia or AOI die shortly after birth from cardiorespiratory insufficiency.Spondylocarpotarsal syndrome (SCT) syndrome is an autosomal recessive condition resulting from FLNB mutations. It is characterized by disproportionate short stature, with vertebral anomalies consisting of block vertebrae, scoliosis, lordosis, carpal and tarsal fusions, joint laxity, clubfeet or flat feet, and mild facial features consisting of round face, frontal bossing, short up-turned nose, cleft palate, conductive hearing loss, and dental enamel hypoplasia. SCT syndrome has also been associated with retinal anomalies and sensorineural deafness. The cataracts and retinal abnormalities described in one family with SCT syndrome were not severe enough to impair vision. Intelligence is normal.Researchers have also identified individuals with multiple joint dislocations and skeletal anomalies whose condition appears to be inherited as an autosomal recessive trait. These individuals often have different radiological findings than those with classic Larsen syndrome. Deficiency of carbohydrate sulfotransferase 3 (CHST3 or also called chondroitin-6-sulfotransferase) has been diagnosed in patients with so-called autosomal recessive Larsen syndrome, humero-spinal dysostosis and spondyloepiphyseal dysplasia Omani type. This condition is now called spondyloepiphyseal dysplasia with dislocations. Key clinical features include congenital dislocation of the knees, elbow joint dysplasia with subluxation and limited extension, hip dysplasia or dislocation, clubfeet, short stature, and kyphoscoliosis developing in late childhood. Analysis of chondroitin sulfate proteoglycans in dermal fibroblasts showed markedly decreased 6-O-sulfation with enhanced 4-O-sulfation, confirming functional impairment of CHST3, and distinguishing these fibroblasts from diastrophic dysplasia sulphate transporter (DTDST)-deficient cells.Larsen of Reunion Island syndrome has clinical manifestations which include dislocations of large joints with ligamentous hyperlaxity, short stature and characteristic facial features (round flat face, prominent forehead, prominent eyes with under-eye shawdows, and small mouth). Radiological features include dislocations of knees, hips, elbows and fingers, advanced carpal ossification, widened metaphyses, particularly at the knees, and radio-ulnar synostosis. Larsen of Reunion Island syndrome is caused by a founder homozygous missense mutation in B4GALT7. Joint hypermobility is present in all patients reported with B4GALT7 mutations, but joint dislocations have only been reported in the patients from Reunion Island. These clinical differences might be explained by different functional consequences of the reported mutations with variable quantitative effect on glycosaminoglycan biosynthesis. B4GALT7 is directly involved in the biosynthesis of proteoglycans.Desbuquois syndrome is a rare genetic disorder characterized by loose or lax joints, distinctive facial features, and short stature with abnormally short arms and legs. Affected individuals may have distinctive facial features including prominent eyes, a small jaw (micrognathia), and a rounded, flattened face. Abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) may also develop. Some individuals have skeletal abnormalities affecting the hands. Desbuquois syndrome is inherited as an autosomal recessive condition due to mutations in calcium-activated nucleotidase 1 (CANT1).Thus, there are four different disorders in the multiple dislocation group, autosomal dominant Larsen syndrome (FLNB), and three autosomal recessive disorders: spondyloepiphyseal dysplasia with dislocations (CHST3), Larsen of Reunion Island (B4GALT7) and Desbuquois dysplasia (CANT1). These latter disorders differ from classic Larsen syndrome and the term autosomal recessive Larsen syndrome should probably be avoided to prevent confusion with clinical disorders resulting from mutations in FLNB.FLNA-related disorders are a group of disorders that occur due to mutations of the filamin A (FLNA) gene. This group includes oto-palato-digita (OPD) syndromes types I and II, frontometaphyseal dysplasia (FMD), and Melnick-Needles syndrome. These disorders are characterized by varying degrees of skeletal malformation (dysplasia). Affected individuals may develop mild symptoms as seen with OPD type I or more severe symptoms as may be associated with FMD or OPD II.Ehlers-Danlos syndrome is a group of hereditary connective tissue disorders. Associated features may vary greatly, depending on the specific form of the disorder present and other factors. However, primary findings may include abnormally flexible, loose joints (articular hypermobility) that may easily become dislocated; unusually loose, thin, “stretchy” skin; and excessive fragility of the skin, blood vessels, and other bodily tissues and membranes.Additional disorders may be characterized by distinctive facial features, multiple dislocations, additional skeletal abnormalities, and/or other findings similar to those associated with Larsen syndrome.
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Diagnosis of Larsen Syndrome
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The diagnosis of Larsen syndrome is made based upon a thorough clinical evaluation, detailed patient history, and identification of characteristic clinical and radiological findings. Radiographic examination can detect the presence and severity of associated skeletal findings. Molecular genetic testing can confirm the presence of the FLNB gene mutation.Prenatal diagnosis of Larsen syndrome may be possible through ultrasound imaging, where reflected sound waves are used to create an image of the developing fetus and reveal characteristic findings based on the clinical experience of the sonographer. Because most cases are sporadic, this diagnosis is seldom made, and confirmation through molecular genetic testing is necessary to confirm the diagnosis. Referral to skilled sonographers who are knowledgeable regarding genetic disorders and skeletal dysplasias may help to confirm this suspicion in prenatal cases with or without subtly affecting parents. Malformations in the skeleton like joint hyperextensions and bifid humerus (bone of the arm), clubbed feet, facial features including depressed nasal bridge, widely separated eyes, prominent forehead and abnormalities in the hands and fingers and a narrow chest with increased amniotic fluid (polyhydramnios) may be suggestive of Larsen syndrome, though other genetic skeletal disorders can also manifest these signs. When suspicion is sufficiently high, sequencing of the FLNB gene can be performed to identify a mutation and come to a definitive diagnosis. When a decision is made to continue the pregnancy with suspected Larsen syndrome, Cesarean section is recommended to prevent trauma to the limbs and the cervical spine during vaginal delivery. Breathing problems due to a small narrow chest are an important issue that should be managed by the neonatologist.
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Diagnosis of Larsen Syndrome. The diagnosis of Larsen syndrome is made based upon a thorough clinical evaluation, detailed patient history, and identification of characteristic clinical and radiological findings. Radiographic examination can detect the presence and severity of associated skeletal findings. Molecular genetic testing can confirm the presence of the FLNB gene mutation.Prenatal diagnosis of Larsen syndrome may be possible through ultrasound imaging, where reflected sound waves are used to create an image of the developing fetus and reveal characteristic findings based on the clinical experience of the sonographer. Because most cases are sporadic, this diagnosis is seldom made, and confirmation through molecular genetic testing is necessary to confirm the diagnosis. Referral to skilled sonographers who are knowledgeable regarding genetic disorders and skeletal dysplasias may help to confirm this suspicion in prenatal cases with or without subtly affecting parents. Malformations in the skeleton like joint hyperextensions and bifid humerus (bone of the arm), clubbed feet, facial features including depressed nasal bridge, widely separated eyes, prominent forehead and abnormalities in the hands and fingers and a narrow chest with increased amniotic fluid (polyhydramnios) may be suggestive of Larsen syndrome, though other genetic skeletal disorders can also manifest these signs. When suspicion is sufficiently high, sequencing of the FLNB gene can be performed to identify a mutation and come to a definitive diagnosis. When a decision is made to continue the pregnancy with suspected Larsen syndrome, Cesarean section is recommended to prevent trauma to the limbs and the cervical spine during vaginal delivery. Breathing problems due to a small narrow chest are an important issue that should be managed by the neonatologist.
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Larsen Syndrome
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Therapies of Larsen Syndrome
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Treatment
The treatment of Larsen 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, orthopedic surgeons, craniofacial specialists, and geneticists who assess and treat skeletal disorders, as well as other specialists who asses and treat hearing problems (audiologists) may need to systematically and comprehensively plan an affected child’s treatment.Treatment of infants with Larsen syndrome consists of joint manipulation and corrective casts or traction. Later, orthopedic surgery may be recommended to correct skeletal dislocations or deformities. Physical therapy may be necessary to strengthen affected joints. Treatment of joint abnormalities often requires long-term therapy.Stabilization of the cervical spine may be necessary in some cases and may include spinal surgery such as the fusion of affected spinal bones.Because of deformities of the cervical spine, special consideration is merited during intubation (placing a breathing tube into the mouth or nose during anesthesia-induction for surgery), which may be necessary for their multiple surgeries. Cervical spine instability and postoperative respiratory complications are potential problems that need to be addressed.For treatment of skeletal malformations and joint dislocations, physical and occupational therapy may be necessary before and after surgery. Reconstructive surgery is appropriate for nasal growth deficiency and for cleft palate, and these patients may also require speech therapy. Breathing (respiratory) problems may require supportive therapy, including ventilator assistance, special feeding techniques, and chest physical therapy.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Therapies of Larsen Syndrome. Treatment
The treatment of Larsen 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, orthopedic surgeons, craniofacial specialists, and geneticists who assess and treat skeletal disorders, as well as other specialists who asses and treat hearing problems (audiologists) may need to systematically and comprehensively plan an affected child’s treatment.Treatment of infants with Larsen syndrome consists of joint manipulation and corrective casts or traction. Later, orthopedic surgery may be recommended to correct skeletal dislocations or deformities. Physical therapy may be necessary to strengthen affected joints. Treatment of joint abnormalities often requires long-term therapy.Stabilization of the cervical spine may be necessary in some cases and may include spinal surgery such as the fusion of affected spinal bones.Because of deformities of the cervical spine, special consideration is merited during intubation (placing a breathing tube into the mouth or nose during anesthesia-induction for surgery), which may be necessary for their multiple surgeries. Cervical spine instability and postoperative respiratory complications are potential problems that need to be addressed.For treatment of skeletal malformations and joint dislocations, physical and occupational therapy may be necessary before and after surgery. Reconstructive surgery is appropriate for nasal growth deficiency and for cleft palate, and these patients may also require speech therapy. Breathing (respiratory) problems may require supportive therapy, including ventilator assistance, special feeding techniques, and chest physical therapy.Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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Larsen Syndrome
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Overview of Laryngeal Dystonia
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SummaryLaryngeal dystonia (LD) is a chronic voice disorder characterized by spasms of the muscles of the voice box (larynx). These muscles control the voice. The spasms can result in tightness in the throat, recurrent hoarseness, and changes in voice quality and/or difficulty speaking. The most frequent sign of this disorder is a sudden, momentary lapse or interruption of the voice. When affected individuals speak, their voice may sound strained, forced, strangled, breathy, or whispery. Speaking becomes less natural, and often requires great effort. In severe cases, an affected individual may be barely able to speak. LD can potentially cause significant quality of life issues for affected individuals impacting both work and social situations. There is no cure for LD, but the disorder can be treated. In most cases, the cause of LD is not known.Introduction LD is a form of dystonia, a group of movement disorders that vary in their symptoms, causes, progression, and treatments. This group of conditions is generally characterized by involuntary muscle contractions that cause abnormal movements and positions (postures). LD is classified as a focal dystonia because it affects a specific part of the body (muscles of the voice box). The most common type of LD is spasmodic dysphonia (SD).
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Overview of Laryngeal Dystonia. SummaryLaryngeal dystonia (LD) is a chronic voice disorder characterized by spasms of the muscles of the voice box (larynx). These muscles control the voice. The spasms can result in tightness in the throat, recurrent hoarseness, and changes in voice quality and/or difficulty speaking. The most frequent sign of this disorder is a sudden, momentary lapse or interruption of the voice. When affected individuals speak, their voice may sound strained, forced, strangled, breathy, or whispery. Speaking becomes less natural, and often requires great effort. In severe cases, an affected individual may be barely able to speak. LD can potentially cause significant quality of life issues for affected individuals impacting both work and social situations. There is no cure for LD, but the disorder can be treated. In most cases, the cause of LD is not known.Introduction LD is a form of dystonia, a group of movement disorders that vary in their symptoms, causes, progression, and treatments. This group of conditions is generally characterized by involuntary muscle contractions that cause abnormal movements and positions (postures). LD is classified as a focal dystonia because it affects a specific part of the body (muscles of the voice box). The most common type of LD is spasmodic dysphonia (SD).
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Laryngeal Dystonia
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Symptoms of Laryngeal Dystonia
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The severity of LD can fluctuate from symptom-free periods with normal voice to severely disabling periods where an affected individual will experience significant difficulty speaking clearly or be barely able to speak. Symptom fluctuation can occur during the same day or from day to day or longer. LD tends to affect normal conversational speech. Several studies have shown that singing, laughing, and yelling, are often unaffected. The two most common types of LD are adductor SD and abductor SD. Adductor SD, the more common type, affects approximately 80% to 90% of individuals. This type affects the muscles that draw the vocal cords together. Adductor SD is characterized by a tight, strained, or harsh sounding voice. Affected individuals may experience difficulties in the voicing of specific vowels sounds such as in the words “eat,” “back,” “I,” “olives,” or “nest”. Abductor SD affects the muscles that draw the vocal cords apart. Abductor SD is characterized by breathy, whispered speech and loss of voice for short periods of time (aphonia). Individuals affected by the abductor type may have difficulty controlling speech after certain sounds (e.g., “h,” “s,” “p,” “t,” or “k”). Some affected individuals may exhibit both types, referred to as mixed SD. Some individuals also experience a vocal tremor, in which the larynx and vocal cords shake potentially affecting speech and making the voice difficult to understand because it sounds shaky or quivery. Other less common manifestations of LD include laryngeal breathing dystonia, singer’s dystonia, repetitive coughing, and others. Onset of LD is usually gradual and the initial symptoms may be mild. Symptoms may progress for the first 2-5 years then generally stabilize. Approximately 15% of patients progress into other forms of dystonia involving the face or neck. The disorder usually remains chronic without marked changes over a period of years, although symptoms may worsen with stress. The number and severity of symptoms varies widely among affected individuals.
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Symptoms of Laryngeal Dystonia. The severity of LD can fluctuate from symptom-free periods with normal voice to severely disabling periods where an affected individual will experience significant difficulty speaking clearly or be barely able to speak. Symptom fluctuation can occur during the same day or from day to day or longer. LD tends to affect normal conversational speech. Several studies have shown that singing, laughing, and yelling, are often unaffected. The two most common types of LD are adductor SD and abductor SD. Adductor SD, the more common type, affects approximately 80% to 90% of individuals. This type affects the muscles that draw the vocal cords together. Adductor SD is characterized by a tight, strained, or harsh sounding voice. Affected individuals may experience difficulties in the voicing of specific vowels sounds such as in the words “eat,” “back,” “I,” “olives,” or “nest”. Abductor SD affects the muscles that draw the vocal cords apart. Abductor SD is characterized by breathy, whispered speech and loss of voice for short periods of time (aphonia). Individuals affected by the abductor type may have difficulty controlling speech after certain sounds (e.g., “h,” “s,” “p,” “t,” or “k”). Some affected individuals may exhibit both types, referred to as mixed SD. Some individuals also experience a vocal tremor, in which the larynx and vocal cords shake potentially affecting speech and making the voice difficult to understand because it sounds shaky or quivery. Other less common manifestations of LD include laryngeal breathing dystonia, singer’s dystonia, repetitive coughing, and others. Onset of LD is usually gradual and the initial symptoms may be mild. Symptoms may progress for the first 2-5 years then generally stabilize. Approximately 15% of patients progress into other forms of dystonia involving the face or neck. The disorder usually remains chronic without marked changes over a period of years, although symptoms may worsen with stress. The number and severity of symptoms varies widely among affected individuals.
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Laryngeal Dystonia
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Causes of Laryngeal Dystonia
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Most cases of LD are idiopathic, which means a cause is not identifiable. Several different factors may be involved in the development of the disorder (multifactorial). Several theories exist that attempt to explain the underlying mechanisms of LD including abnormal functioning of portions of the brain involved in muscle control, or imbalances in neurotransmitters. Neurotransmitters are chemicals that modify, amplify, or transmit nerve impulses from one brain cell (neuron) to another, enabling nerve cells to communicate. Although the underlying mechanisms and causes of LD are not well understood, research is ongoing to determine the specific roles that genetic, environmental, and other factors ultimately play in the development of the disorder. There are reports in the medical literature that suggest LD may develop following specific factors such as an upper respiratory infection or bronchitis, trauma or surgery, or exposure to certain drugs and/or toxins. However, such theories are controversial because there is no scientific evidence conclusively linking these factors to LD. Genetic factors are believed to play a role in some cases, especially in individuals who have a relative with LD or another form of dystonia. These individuals may have a genetic susceptibility to developing the disorder. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but the disorder may not be expressed unless it is triggered or activated by other genetic modifiers or environmental factors (complex genetics). More research is necessary to determine what role this or other genes have in the development of LD.
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Causes of Laryngeal Dystonia. Most cases of LD are idiopathic, which means a cause is not identifiable. Several different factors may be involved in the development of the disorder (multifactorial). Several theories exist that attempt to explain the underlying mechanisms of LD including abnormal functioning of portions of the brain involved in muscle control, or imbalances in neurotransmitters. Neurotransmitters are chemicals that modify, amplify, or transmit nerve impulses from one brain cell (neuron) to another, enabling nerve cells to communicate. Although the underlying mechanisms and causes of LD are not well understood, research is ongoing to determine the specific roles that genetic, environmental, and other factors ultimately play in the development of the disorder. There are reports in the medical literature that suggest LD may develop following specific factors such as an upper respiratory infection or bronchitis, trauma or surgery, or exposure to certain drugs and/or toxins. However, such theories are controversial because there is no scientific evidence conclusively linking these factors to LD. Genetic factors are believed to play a role in some cases, especially in individuals who have a relative with LD or another form of dystonia. These individuals may have a genetic susceptibility to developing the disorder. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but the disorder may not be expressed unless it is triggered or activated by other genetic modifiers or environmental factors (complex genetics). More research is necessary to determine what role this or other genes have in the development of LD.
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Laryngeal Dystonia
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Affects of Laryngeal Dystonia
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LD occurs more often in females than males and can affect individuals of all ethnic backgrounds. Onset can occur at any age, but usually occurs between 30 and 60 years of age. The exact incidence or prevalence of the disorder is unknown. LD is estimated to affect approximately 50,000 people in North America. However, determining the true frequency of LD in the general population is difficult because many cases are misdiagnosed or go undiagnosed.
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Affects of Laryngeal Dystonia. LD occurs more often in females than males and can affect individuals of all ethnic backgrounds. Onset can occur at any age, but usually occurs between 30 and 60 years of age. The exact incidence or prevalence of the disorder is unknown. LD is estimated to affect approximately 50,000 people in North America. However, determining the true frequency of LD in the general population is difficult because many cases are misdiagnosed or go undiagnosed.
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Laryngeal Dystonia
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Related disorders of Laryngeal Dystonia
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Symptoms of the following disorders can be similar to those of LD. Comparisons may be useful for a differential diagnosis: Muscle tension dysphonia is a condition characterized by hoarseness or a strained, rough quality of the voice. Symptoms may become progressively worse with use and improve with rest (i.e. not speaking). Muscle tension dysphonia is caused by abnormal contractions of the muscles of the voice box that control the voice. It is common in individuals who use their voice frequently and may result from straining, squeezing, or pushing these muscles inappropriately. Although LD and muscle tension dysphonia are considered separate disorders, it can be difficult to tell them apart, even for experts. Some experts believe that symptoms of LD and muscle tension dysphonia can co-occur. However, unlike LD, muscle tension dysphonia is reversible with voice therapy. LD is often combined with tremor (probably more than 40% of patients have both). Tremors are neurological disorders characterized by rhythmical shaking of a body region, most often of the hands or arms. Tremor may be seen as involuntary shaking or trembling of the affected area. Other motor symptoms may be present including an unsteady manner of walking due to an inability to coordinate voluntary movements (ataxia). The primary symptom is a fine or coarse rhythmic tremor that occurs approximately 4 to 12 times per second. In some people, tremor may affect the tongue and/or the vocal cords, leading difficulty speaking (dysarthria). It can also affect the muscles of the neck, causing the head to shake. The exact, underlying cause of most tremors is not fully understood and is most likely multifactorial, which means that several factors, such as genetic and environmental ones, all play a role in the development of the disorder. The rhythmical sound of voice tremor is sometimes difficult to distinguish from the semi-rhythmical voice interruptions in LD (For more information, choose “essential tremor” as your search term in the Rare Disease Database.) Chronic stuttering is a common speech disorder characterized by an abnormal speech pattern that is composed of repetitions, prolongations, and unusual hesitations that disrupt the rhythmic flow of speech. Affected children usually know what they want to say, but have difficulty or are unable to say it. The disorder usually appears before age 12 and often affects more than one family member (familial). Although stuttering usually resolves on its own (spontaneously) before adolescence, it can persist into adulthood. Most likely, chronic stuttering is caused by a variety of factors.
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Related disorders of Laryngeal Dystonia. Symptoms of the following disorders can be similar to those of LD. Comparisons may be useful for a differential diagnosis: Muscle tension dysphonia is a condition characterized by hoarseness or a strained, rough quality of the voice. Symptoms may become progressively worse with use and improve with rest (i.e. not speaking). Muscle tension dysphonia is caused by abnormal contractions of the muscles of the voice box that control the voice. It is common in individuals who use their voice frequently and may result from straining, squeezing, or pushing these muscles inappropriately. Although LD and muscle tension dysphonia are considered separate disorders, it can be difficult to tell them apart, even for experts. Some experts believe that symptoms of LD and muscle tension dysphonia can co-occur. However, unlike LD, muscle tension dysphonia is reversible with voice therapy. LD is often combined with tremor (probably more than 40% of patients have both). Tremors are neurological disorders characterized by rhythmical shaking of a body region, most often of the hands or arms. Tremor may be seen as involuntary shaking or trembling of the affected area. Other motor symptoms may be present including an unsteady manner of walking due to an inability to coordinate voluntary movements (ataxia). The primary symptom is a fine or coarse rhythmic tremor that occurs approximately 4 to 12 times per second. In some people, tremor may affect the tongue and/or the vocal cords, leading difficulty speaking (dysarthria). It can also affect the muscles of the neck, causing the head to shake. The exact, underlying cause of most tremors is not fully understood and is most likely multifactorial, which means that several factors, such as genetic and environmental ones, all play a role in the development of the disorder. The rhythmical sound of voice tremor is sometimes difficult to distinguish from the semi-rhythmical voice interruptions in LD (For more information, choose “essential tremor” as your search term in the Rare Disease Database.) Chronic stuttering is a common speech disorder characterized by an abnormal speech pattern that is composed of repetitions, prolongations, and unusual hesitations that disrupt the rhythmic flow of speech. Affected children usually know what they want to say, but have difficulty or are unable to say it. The disorder usually appears before age 12 and often affects more than one family member (familial). Although stuttering usually resolves on its own (spontaneously) before adolescence, it can persist into adulthood. Most likely, chronic stuttering is caused by a variety of factors.
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Laryngeal Dystonia
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Diagnosis of Laryngeal Dystonia
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The diagnosis of LD usually involves careful assessment of the voice and speaking under different conditions by a speech pathologist, otolaryngologist, or neurologist. It also includes inspection of the voice box (laryngoscopy) to rule out structural abnormalities of the vocal cords such as nodules, polyps, or tumors.
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Diagnosis of Laryngeal Dystonia. The diagnosis of LD usually involves careful assessment of the voice and speaking under different conditions by a speech pathologist, otolaryngologist, or neurologist. It also includes inspection of the voice box (laryngoscopy) to rule out structural abnormalities of the vocal cords such as nodules, polyps, or tumors.
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Laryngeal Dystonia
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Therapies of Laryngeal Dystonia
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Treatment
There is no cure for LD. Treatment is aimed at the symptoms in each individual. Psychological support and counseling can help individuals cope with depression, anxiety or other psychological issues associated with LD. Botulinum toxin therapy is often used for LD. The drug works by blocking nerve activity that controls muscles. The result is that muscle activity is not as strong. The drug is injected into the vocal cords every three or four months. Some individuals can wait longer between injections before symptoms return and more injections are needed. The degree of effectiveness of Botulinum toxin will differ in each individual case. Botulinum toxin is approved by the Food and Drug Administration (FDA) for some types of dystonia, but not LD. However, it is widely used off label to treat all forms of dystonia. Speech or voice therapy such as voice relaxation techniques may be beneficial for some individuals with LD, especially those with mild cases of the disorder. Speech or voice therapy may also be effective in treating side effects associated with other treatments such as Botulinum toxin (adjuvant therapy). Some individuals may benefit from using machines or devices that amplify the voice. Oral medications have been used to treat forms of dystonia such as LD. However, there are no oral medications that are FDA approved for such use. Such medications include dopaminergic agents (levodopa), anticholinergic agents (benztropine, trihexyphenidyl), baclofen, and clonazepam. These drugs act in various way to reduce muscle or nerve activity, but are often associated with side effects. If other therapeutic options are ineffective, contraindicated, or no longer effective after initially providing relief, then surgery may be recommended. Surgery may be aimed at separating the vocal cords or weakening the affected muscles of the larynx. Specific procedures include thyroplasty or selective laryngeal adductor denervation-reinnervation. Decisions concerning the use of particular drug regimens and/or other treatments such as surgery should be made by physicians and other members of the health care team in careful consultation with parents or a patient based upon the specifics of an individual case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
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Therapies of Laryngeal Dystonia. Treatment
There is no cure for LD. Treatment is aimed at the symptoms in each individual. Psychological support and counseling can help individuals cope with depression, anxiety or other psychological issues associated with LD. Botulinum toxin therapy is often used for LD. The drug works by blocking nerve activity that controls muscles. The result is that muscle activity is not as strong. The drug is injected into the vocal cords every three or four months. Some individuals can wait longer between injections before symptoms return and more injections are needed. The degree of effectiveness of Botulinum toxin will differ in each individual case. Botulinum toxin is approved by the Food and Drug Administration (FDA) for some types of dystonia, but not LD. However, it is widely used off label to treat all forms of dystonia. Speech or voice therapy such as voice relaxation techniques may be beneficial for some individuals with LD, especially those with mild cases of the disorder. Speech or voice therapy may also be effective in treating side effects associated with other treatments such as Botulinum toxin (adjuvant therapy). Some individuals may benefit from using machines or devices that amplify the voice. Oral medications have been used to treat forms of dystonia such as LD. However, there are no oral medications that are FDA approved for such use. Such medications include dopaminergic agents (levodopa), anticholinergic agents (benztropine, trihexyphenidyl), baclofen, and clonazepam. These drugs act in various way to reduce muscle or nerve activity, but are often associated with side effects. If other therapeutic options are ineffective, contraindicated, or no longer effective after initially providing relief, then surgery may be recommended. Surgery may be aimed at separating the vocal cords or weakening the affected muscles of the larynx. Specific procedures include thyroplasty or selective laryngeal adductor denervation-reinnervation. Decisions concerning the use of particular drug regimens and/or other treatments such as surgery should be made by physicians and other members of the health care team in careful consultation with parents or a patient based upon the specifics of an individual case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
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Laryngeal Dystonia
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Overview of Laurence-Moon Syndrome
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SummaryLaurence-Moon syndrome (LNMS) is a genetic condition that results in a complex association of problems that affect several different body parts. People with LNMS may have difficulties with functions of the brain, eyes, ears, stomach, kidneys, hands and feet. They often also demonstrate a tendency to short stature and obesity. Because of the many complications seen in this condition, it is important that the patient has a strong, comprehensive health care team.IntroductionLNMS was later termed Laurence-Moon-Bardet-Biedl syndrome because of similarities with Bardet-Biedl syndrome (BBS). It is often considered, but still debated, whether BBS is a distinct condition. Arguments are based on differences in the underlying genetic causes of these the disorders (see Related Disorders). These two disorders also share similarity to Oliver-McFarlane syndrome (OMS). All three conditions are characterized by progressive blindness, obesity, and learning disabilities.Differences in the clinical presentation include subtle but important hints as offered in the following examples. LNMS is associated with difficulty in controlling body movements, which is also seen in adolescent and adult patients with OMS and less frequently in BBS. LNMS and OMS are associated with abnormal pituitary gland function. BBS is associated with extra fingers and toes, and kidney and liver dysfunction. OMS is associated with abnormal growth of eyelashes and eyebrows. Neither LNMS nor BBS are generally associated with such difficulty.Of important note to patients and physicians, the practical management of these conditions is similar. These conditions are all managed with close attention to each individual patient’s symptoms. This contributes to the ability to group LNMS, BBS, and OMS together in clinical settings. For the purposes of the description of these entities by what is known of their genetic cause, we have drawn stricter differentiating lines between them and offer distinct articles on each related disorder.
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Overview of Laurence-Moon Syndrome. SummaryLaurence-Moon syndrome (LNMS) is a genetic condition that results in a complex association of problems that affect several different body parts. People with LNMS may have difficulties with functions of the brain, eyes, ears, stomach, kidneys, hands and feet. They often also demonstrate a tendency to short stature and obesity. Because of the many complications seen in this condition, it is important that the patient has a strong, comprehensive health care team.IntroductionLNMS was later termed Laurence-Moon-Bardet-Biedl syndrome because of similarities with Bardet-Biedl syndrome (BBS). It is often considered, but still debated, whether BBS is a distinct condition. Arguments are based on differences in the underlying genetic causes of these the disorders (see Related Disorders). These two disorders also share similarity to Oliver-McFarlane syndrome (OMS). All three conditions are characterized by progressive blindness, obesity, and learning disabilities.Differences in the clinical presentation include subtle but important hints as offered in the following examples. LNMS is associated with difficulty in controlling body movements, which is also seen in adolescent and adult patients with OMS and less frequently in BBS. LNMS and OMS are associated with abnormal pituitary gland function. BBS is associated with extra fingers and toes, and kidney and liver dysfunction. OMS is associated with abnormal growth of eyelashes and eyebrows. Neither LNMS nor BBS are generally associated with such difficulty.Of important note to patients and physicians, the practical management of these conditions is similar. These conditions are all managed with close attention to each individual patient’s symptoms. This contributes to the ability to group LNMS, BBS, and OMS together in clinical settings. For the purposes of the description of these entities by what is known of their genetic cause, we have drawn stricter differentiating lines between them and offer distinct articles on each related disorder.
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Symptoms of Laurence-Moon Syndrome
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The major signs that people present with which raise the suspicion that they may have LNMS are summarized below. The individual components of this condition can notably vary greatly in severity however.Physicians may begin to investigate the diagnosis of a genetic condition when they identify structural abnormalities of the hands and feet. Abnormalities commonly include both too many and too few fingers or toes. Between LMS and BBS, it is the people with BBS that are born with an extra digit near the pinky or an extra toe near the fifth “little” toe. In medical terminology, this is described as a ‘postaxial polydactyly’. Interestingly, the presence of an extra toe is more common than that of an extra finger. In patients with LNMS, fingers and toes may however have some degree of webbing, which is referred to as “syndactyly”. Syndactyly is especially common between the second and third toes. Less often, fingers and toes may be abnormally short in length. This finding is called a “brachydactyly” and can be especially expected to affect the thumb. The thumb may additionally be placed subtly closer to the wrist than expected. Finally, the feet may also be overall short in length, of wide width, and carry a flat arch. In regard to additional skeletal changes, patients with LNMS may notice or be told that they have some slight changes in the basic shape of their teeth. Teeth are made up of two major segments, the body and roots. Patients with LNMS may experience taurodontism, in which the development of tooth’s body is enlarged relative to the roots. Most commonly, it is the flat, molar teeth at the back of the mouth that are affected. Most commonly, this condition is noted at the time of first dental x-rays, where the teeth will appear more rectangular than expected.People with LNMS are also often burdened by problems with the coordination of their body’s movements. Many patients report a significant degree of clumsiness and often walk with legs in a wide-based stance. Walking heel-to-toe may be difficult. Such impairment is specifically the result of problems with the cerebellum, the sub-section of the brain responsible for coordination. The dysfunction of the cerebellum can lead to dysfunction of the spinal nerve conduction pathways that communicate signals between the brain and muscles. This results in a complex constellation of movement irregularities. The term ataxia is used to describe this loss of control over coordinated bodily movements, and can make it difficult to speak, eat, walk, and maintain balance. Ataxia is accompanied by spasticity, a continuous contraction of muscles in an involuntary manner. The term contracture is used to describe a hardening and shortening of muscles and surrounding connective tissue.People with LNMS also often experience other problems related to functions controlled by the brain.Most patients with LNMS will experience a gradual loss of vision. The term “retinitis pigmentosa” is used to describe the particular, gradual-onset, vision loss that progresses according to a particular pattern. Retinitis pigmentosa begins with a night blindness that worsens with a loss of the ability to distinguish colors from one another, finally deteriorating into “tunnel vision”. (For more information, choose “Retinitis Pigmentosa” as your search term in the Rare Disease Database).Mild-to-moderate learning difficulties are common in individuals with LNMS. Often, learning disabilities are attributed to weakened cognitive capacity. Some individuals affected with LNMS may have true learning disabilities due to dysfunction of brain development. However, it is important to be sure that suspected disabilities (such as delayed speech or reading skills) are not due to underlying visual impairment. If the learning disability is rooted in neurological impairments, they are often associated with symptoms of poor coordination, gross and fine motor skills, and social milestones in childhood such as inability to play complicated games with other children.People living with LNMS have been found to have smaller than average size anterior pituitary glands and can suffer from a series of different complications as a result. The anterior portion of the pituitary gland is responsible for regulating many functions including the body’s metabolism, emotional responses to stressors, physical bodily growth, and reproductive capacity. The body’s metabolism is controlled by thyroid stimulating hormone. With low levels of thyroid stimulating hormone, people will experience many different symptoms: fatigue, sensitivity to cold, poor ability to concentrate, weight gain, constipation, shortness of breath. The body will potentially change its common behaviors. For example, skin will become dry and course, hair will fall out, reflexes will slow.People with LNMS often have decreased levels of the sex hormones estrogen and testosterone. This is also due to the small size of the pituitary gland, a small gland located in the brain that is responsible for producing the chemical signals that orchestrate the production of sex hormones. As a result of a weak signal to produce estrogen and testosterone, the reproductive organs of both men and women living with LNMS may be underdeveloped, resulting in reduced fertility or even infertility. Males with LNMS may have an underdeveloped set of testicles that may be undescended. In females, the uterus, fallopian tubes, and ovaries are often underdeveloped. Menstruation cycles can be delayed from the average first age of onset and when they do begin, may follow an irregular cycle. Other less common features that have been reported in patients living with LNMS include a skull shape shorter than average, termed “brachycephaly” and electrical abnormalities of the heart. (For more information, choose “congenital heart block” as your search term in the Rare Disease Database). People may also experience a loss of hearing, increased incidence of diabetes, liver fibrosis, and urinary and genital structural malformations.
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Symptoms of Laurence-Moon Syndrome. The major signs that people present with which raise the suspicion that they may have LNMS are summarized below. The individual components of this condition can notably vary greatly in severity however.Physicians may begin to investigate the diagnosis of a genetic condition when they identify structural abnormalities of the hands and feet. Abnormalities commonly include both too many and too few fingers or toes. Between LMS and BBS, it is the people with BBS that are born with an extra digit near the pinky or an extra toe near the fifth “little” toe. In medical terminology, this is described as a ‘postaxial polydactyly’. Interestingly, the presence of an extra toe is more common than that of an extra finger. In patients with LNMS, fingers and toes may however have some degree of webbing, which is referred to as “syndactyly”. Syndactyly is especially common between the second and third toes. Less often, fingers and toes may be abnormally short in length. This finding is called a “brachydactyly” and can be especially expected to affect the thumb. The thumb may additionally be placed subtly closer to the wrist than expected. Finally, the feet may also be overall short in length, of wide width, and carry a flat arch. In regard to additional skeletal changes, patients with LNMS may notice or be told that they have some slight changes in the basic shape of their teeth. Teeth are made up of two major segments, the body and roots. Patients with LNMS may experience taurodontism, in which the development of tooth’s body is enlarged relative to the roots. Most commonly, it is the flat, molar teeth at the back of the mouth that are affected. Most commonly, this condition is noted at the time of first dental x-rays, where the teeth will appear more rectangular than expected.People with LNMS are also often burdened by problems with the coordination of their body’s movements. Many patients report a significant degree of clumsiness and often walk with legs in a wide-based stance. Walking heel-to-toe may be difficult. Such impairment is specifically the result of problems with the cerebellum, the sub-section of the brain responsible for coordination. The dysfunction of the cerebellum can lead to dysfunction of the spinal nerve conduction pathways that communicate signals between the brain and muscles. This results in a complex constellation of movement irregularities. The term ataxia is used to describe this loss of control over coordinated bodily movements, and can make it difficult to speak, eat, walk, and maintain balance. Ataxia is accompanied by spasticity, a continuous contraction of muscles in an involuntary manner. The term contracture is used to describe a hardening and shortening of muscles and surrounding connective tissue.People with LNMS also often experience other problems related to functions controlled by the brain.Most patients with LNMS will experience a gradual loss of vision. The term “retinitis pigmentosa” is used to describe the particular, gradual-onset, vision loss that progresses according to a particular pattern. Retinitis pigmentosa begins with a night blindness that worsens with a loss of the ability to distinguish colors from one another, finally deteriorating into “tunnel vision”. (For more information, choose “Retinitis Pigmentosa” as your search term in the Rare Disease Database).Mild-to-moderate learning difficulties are common in individuals with LNMS. Often, learning disabilities are attributed to weakened cognitive capacity. Some individuals affected with LNMS may have true learning disabilities due to dysfunction of brain development. However, it is important to be sure that suspected disabilities (such as delayed speech or reading skills) are not due to underlying visual impairment. If the learning disability is rooted in neurological impairments, they are often associated with symptoms of poor coordination, gross and fine motor skills, and social milestones in childhood such as inability to play complicated games with other children.People living with LNMS have been found to have smaller than average size anterior pituitary glands and can suffer from a series of different complications as a result. The anterior portion of the pituitary gland is responsible for regulating many functions including the body’s metabolism, emotional responses to stressors, physical bodily growth, and reproductive capacity. The body’s metabolism is controlled by thyroid stimulating hormone. With low levels of thyroid stimulating hormone, people will experience many different symptoms: fatigue, sensitivity to cold, poor ability to concentrate, weight gain, constipation, shortness of breath. The body will potentially change its common behaviors. For example, skin will become dry and course, hair will fall out, reflexes will slow.People with LNMS often have decreased levels of the sex hormones estrogen and testosterone. This is also due to the small size of the pituitary gland, a small gland located in the brain that is responsible for producing the chemical signals that orchestrate the production of sex hormones. As a result of a weak signal to produce estrogen and testosterone, the reproductive organs of both men and women living with LNMS may be underdeveloped, resulting in reduced fertility or even infertility. Males with LNMS may have an underdeveloped set of testicles that may be undescended. In females, the uterus, fallopian tubes, and ovaries are often underdeveloped. Menstruation cycles can be delayed from the average first age of onset and when they do begin, may follow an irregular cycle. Other less common features that have been reported in patients living with LNMS include a skull shape shorter than average, termed “brachycephaly” and electrical abnormalities of the heart. (For more information, choose “congenital heart block” as your search term in the Rare Disease Database). People may also experience a loss of hearing, increased incidence of diabetes, liver fibrosis, and urinary and genital structural malformations.
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Causes of Laurence-Moon Syndrome
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LNMS is most commonly attributed to changes (mutations) in the PNPLA6 gene. Genes are specific sequences in DNA that provide instructions for the production of proteins. Proteins serve as the body’s cellular machinery and building blocks. The PNPLA6 gene is responsible for the production of proteins that drive the breakdown of cell membranes. The PNPLA6 protein is an enzyme that is thought to drive the growth of nerve and non-nerve cells as they grow and mature. This gene is notably associated not only with LNMS but also Boucher-Neuhauser syndrome, Gordon-Holmes syndrome, and spastic paraplegia type 39. These conditions are described in brief under the Related Disorders section.LNMS follows an autosomal recessive pattern of inheritance. 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.
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Causes of Laurence-Moon Syndrome. LNMS is most commonly attributed to changes (mutations) in the PNPLA6 gene. Genes are specific sequences in DNA that provide instructions for the production of proteins. Proteins serve as the body’s cellular machinery and building blocks. The PNPLA6 gene is responsible for the production of proteins that drive the breakdown of cell membranes. The PNPLA6 protein is an enzyme that is thought to drive the growth of nerve and non-nerve cells as they grow and mature. This gene is notably associated not only with LNMS but also Boucher-Neuhauser syndrome, Gordon-Holmes syndrome, and spastic paraplegia type 39. These conditions are described in brief under the Related Disorders section.LNMS follows an autosomal recessive pattern of inheritance. 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.
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Affects of Laurence-Moon Syndrome
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Males and females are affected equally. In North America, it is estimated that 1 in 100,000 people is affected by LNMS. Kuwait and Newfoundland are two places where the number of people affects with LNMS are comparatively high.
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Affects of Laurence-Moon Syndrome. Males and females are affected equally. In North America, it is estimated that 1 in 100,000 people is affected by LNMS. Kuwait and Newfoundland are two places where the number of people affects with LNMS are comparatively high.
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Related disorders of Laurence-Moon Syndrome
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The following conditions have notably been considered in the differential diagnosis for patients with LNMS given the similar presentation of symptoms. They are only briefly summarized here. Without genetic testing, it can be very difficult to clinically differentiate these conditions.Bardet-Biedl Syndrome (BBS)
BBS is characterized by central obesity, intellectual impairment with kidney anomalies, polydactyly, retinal degeneration and hypogenitalism. This condition is associated with a series of different mutations, especially in proteins involved in the assembly of the BBSome. The BBSome is an eight-protein complex that serves in the assembly of cilia, slender lashes that extend from cell bodies. Cilia serve various functions from helping the cell move to monitoring chemicals in its environment. (For more information, choose “Bardet-Biedl Syndrome” as your search term in the Rare Disease Database).Boucher-Neuhauser Syndrome (BNS)
BNS is a condition that results in ataxic movement abnormalities and a hypogonadotropic hypogonadism (poor sexual development resulting from poor pituitary gland function). People with BNS often also have chorioretinal degeneration, resulting in vision loss. They may sometimes demonstrate developmental delays or rapid side-to-side movement of the eyes called nystagmus. This condition has been associated with mutations in the PNPLA6 gene and with another gene called RNF216. RNF216 is responsible for the tagging of cell proteins destined for degradation. Gordon-Holmes Syndrome (GHS)
GHS describes the association of ataxic movement abnormalities with hypogonadotropic hypogonadism as describes above. As adults, people with GHS demonstrate neurodegenerative changes. A subset of patients with GHS may demonstrate exaggerated, brisk reflexes. This condition is associated with mutations in the PNPLA6 gene.Joubert Syndrome
Joubert syndrome is a severe disorder in which children do not live beyond three-years of age. People born with this condition experience ataxic and flaccid movement difficulties, abnormalities in the movements of the eyes, mouth and difficulty breathing. They experience retinal dystrophy, developmental delays and multiple visceral organ problems. They have characteristic body features that include broad foreheads, arched eyebrows, ptosis, hypertelorism, low-set ears, and a triangular mouth. (For more information on this condition, search for “Joubert” in the Rare Disease Database.) McKusick-Kaufman Syndrome (MSK)
MSK is a condition associated with polydactyly, heart, genital and urinary anatomy abnormalities. Female patients may have an absent vaginal with mucoid accumulations identifiable within an intact uterus within the abdomen. They may alternatively have a double vaginal or uterine structures. Males may have undescended testicles, abnormal opening of the urethra over the penile head. Either sex may have fibrosis or degeneration of their ureters, the conduit for urine formed by the kidneys destined for storage in the bladder.Meckel Syndrome
Meckel Syndrome is another ciliopathy like BBS. It however describes the association of retinal degeneration, polydactyly, and renal cysts, poor development of the brain and liver as well as poor lung function resulting from low amniotic fluid volumes within the placenta during the pregnancy. (For more information on this condition, search for “Meckel” in the Rare Disease Database.) Oliver-McFarlane Syndrome (OMS)
OMS describes an association of trichomegaly, chorioretinal dystrophy, intellectual disability, and hypopituitarism. Patients often have associated physical features including a large frontal skull, prominent chin, mid-front scalp hair loss, bushy eyebrows, and long eyelashes. This condition is associated with mutations in the PNPLA6 gene. Spastic Paraplegia Type 39 (SPG39)
SPG39 describes the association of upper motor neuron involvement and/or cerebellar ataxia, peripheral neuropathy, and/or reduced cognitive capacity. This condition is associated with mutations in the PNPLA6 gene.
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Related disorders of Laurence-Moon Syndrome. The following conditions have notably been considered in the differential diagnosis for patients with LNMS given the similar presentation of symptoms. They are only briefly summarized here. Without genetic testing, it can be very difficult to clinically differentiate these conditions.Bardet-Biedl Syndrome (BBS)
BBS is characterized by central obesity, intellectual impairment with kidney anomalies, polydactyly, retinal degeneration and hypogenitalism. This condition is associated with a series of different mutations, especially in proteins involved in the assembly of the BBSome. The BBSome is an eight-protein complex that serves in the assembly of cilia, slender lashes that extend from cell bodies. Cilia serve various functions from helping the cell move to monitoring chemicals in its environment. (For more information, choose “Bardet-Biedl Syndrome” as your search term in the Rare Disease Database).Boucher-Neuhauser Syndrome (BNS)
BNS is a condition that results in ataxic movement abnormalities and a hypogonadotropic hypogonadism (poor sexual development resulting from poor pituitary gland function). People with BNS often also have chorioretinal degeneration, resulting in vision loss. They may sometimes demonstrate developmental delays or rapid side-to-side movement of the eyes called nystagmus. This condition has been associated with mutations in the PNPLA6 gene and with another gene called RNF216. RNF216 is responsible for the tagging of cell proteins destined for degradation. Gordon-Holmes Syndrome (GHS)
GHS describes the association of ataxic movement abnormalities with hypogonadotropic hypogonadism as describes above. As adults, people with GHS demonstrate neurodegenerative changes. A subset of patients with GHS may demonstrate exaggerated, brisk reflexes. This condition is associated with mutations in the PNPLA6 gene.Joubert Syndrome
Joubert syndrome is a severe disorder in which children do not live beyond three-years of age. People born with this condition experience ataxic and flaccid movement difficulties, abnormalities in the movements of the eyes, mouth and difficulty breathing. They experience retinal dystrophy, developmental delays and multiple visceral organ problems. They have characteristic body features that include broad foreheads, arched eyebrows, ptosis, hypertelorism, low-set ears, and a triangular mouth. (For more information on this condition, search for “Joubert” in the Rare Disease Database.) McKusick-Kaufman Syndrome (MSK)
MSK is a condition associated with polydactyly, heart, genital and urinary anatomy abnormalities. Female patients may have an absent vaginal with mucoid accumulations identifiable within an intact uterus within the abdomen. They may alternatively have a double vaginal or uterine structures. Males may have undescended testicles, abnormal opening of the urethra over the penile head. Either sex may have fibrosis or degeneration of their ureters, the conduit for urine formed by the kidneys destined for storage in the bladder.Meckel Syndrome
Meckel Syndrome is another ciliopathy like BBS. It however describes the association of retinal degeneration, polydactyly, and renal cysts, poor development of the brain and liver as well as poor lung function resulting from low amniotic fluid volumes within the placenta during the pregnancy. (For more information on this condition, search for “Meckel” in the Rare Disease Database.) Oliver-McFarlane Syndrome (OMS)
OMS describes an association of trichomegaly, chorioretinal dystrophy, intellectual disability, and hypopituitarism. Patients often have associated physical features including a large frontal skull, prominent chin, mid-front scalp hair loss, bushy eyebrows, and long eyelashes. This condition is associated with mutations in the PNPLA6 gene. Spastic Paraplegia Type 39 (SPG39)
SPG39 describes the association of upper motor neuron involvement and/or cerebellar ataxia, peripheral neuropathy, and/or reduced cognitive capacity. This condition is associated with mutations in the PNPLA6 gene.
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Diagnosis of Laurence-Moon Syndrome
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Due to its highly variable clinical presentation of the condition, no formal diagnostic criteria have been established for LMS or, for that matter, any PNPLA6-related disorders. LMS is definitively diagnosed with molecular testing for mutations in the PNPLA6 gene.
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Diagnosis of Laurence-Moon Syndrome. Due to its highly variable clinical presentation of the condition, no formal diagnostic criteria have been established for LMS or, for that matter, any PNPLA6-related disorders. LMS is definitively diagnosed with molecular testing for mutations in the PNPLA6 gene.
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Therapies of Laurence-Moon Syndrome
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Treatment
The treatments available for LNMS are oriented towards managing the manifestations of the illness. People with LNMS often experience ataxia, spasticity, and contracture that compromise their ability to move comfortably. Physical therapy aimed towards improving strength and agility is key. Often walking can be assisted by tools such as ankle-foot orthotic braces, weight-bearing walkers, etc. Physical exercise can reduce the symptoms of ataxia, spasticity, and prevent contracture. A dedicated regimen of nutritious, well-balanced meals and regular exercise is recommended to avoid some of the less common but equally severe aspects that have been noted to affect patients with LNMS. There is most notably, an increased incidence of diabetes and abnormal cholesterol levels in patients with LNMS.The poor functional capacity of the anterior pituitary gland that results in slowed metabolism, poor growth, and impaired fertility can be managed with hormone replacement therapies. Levothyroxine is a medication that mimics the functions of the thyroid hormone and can aid in speeding up the metabolism of the body, resulting in reduced symptoms of lethargy, hair loss, and obesity. Growth hormone supplementation can be offered to reduce the burden of short stature in patients identified as children.It is important for patients with LNMS to be under the care of an ophthalmologist. There is no cure for the vision problems that accompanies LNMS, but ophthalmologists can help create corrective lenses against developing problems. Individuals with LNMS should undergo regular ophthalmologic examinations and keep up with their changing prescriptions. Since visual impairment is a major hurdle to learning in the classroom, special services might be organized on an individual basis between a child’s physician and their school.For patients living with LNMS, it is important to recognize that the many difficulties described above are associated with the brain’s neurological function. It is thus important to protect baseline function capacity of the brain. Inactivity and obesity exacerbate neuropathy. Alcohol and recreational drugs should be avoided. Generally, very little information exists to guide women living with rare diseases who are interested in becoming pregnant. Pregnancy is well known to take many physical demands on a woman’s body and women who are living with LNMS are generally warned that symptoms of ataxia may worsen or even develop for the first time during pregnancy. Pregnant women with LNMS should be followed closely by obstetricians that are well trained in dealing with high-risk pregnancies.Patients living with LNMS experience alterations to the shape of their teeth. Taurodontism is generally noted at the dental office at the time of first x-rays. Extra care may be needed in brushing and cleaning all aspects of the affected teeth, and dentists may need special tools to examine all aspects of the affected teeth.
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Therapies of Laurence-Moon Syndrome. Treatment
The treatments available for LNMS are oriented towards managing the manifestations of the illness. People with LNMS often experience ataxia, spasticity, and contracture that compromise their ability to move comfortably. Physical therapy aimed towards improving strength and agility is key. Often walking can be assisted by tools such as ankle-foot orthotic braces, weight-bearing walkers, etc. Physical exercise can reduce the symptoms of ataxia, spasticity, and prevent contracture. A dedicated regimen of nutritious, well-balanced meals and regular exercise is recommended to avoid some of the less common but equally severe aspects that have been noted to affect patients with LNMS. There is most notably, an increased incidence of diabetes and abnormal cholesterol levels in patients with LNMS.The poor functional capacity of the anterior pituitary gland that results in slowed metabolism, poor growth, and impaired fertility can be managed with hormone replacement therapies. Levothyroxine is a medication that mimics the functions of the thyroid hormone and can aid in speeding up the metabolism of the body, resulting in reduced symptoms of lethargy, hair loss, and obesity. Growth hormone supplementation can be offered to reduce the burden of short stature in patients identified as children.It is important for patients with LNMS to be under the care of an ophthalmologist. There is no cure for the vision problems that accompanies LNMS, but ophthalmologists can help create corrective lenses against developing problems. Individuals with LNMS should undergo regular ophthalmologic examinations and keep up with their changing prescriptions. Since visual impairment is a major hurdle to learning in the classroom, special services might be organized on an individual basis between a child’s physician and their school.For patients living with LNMS, it is important to recognize that the many difficulties described above are associated with the brain’s neurological function. It is thus important to protect baseline function capacity of the brain. Inactivity and obesity exacerbate neuropathy. Alcohol and recreational drugs should be avoided. Generally, very little information exists to guide women living with rare diseases who are interested in becoming pregnant. Pregnancy is well known to take many physical demands on a woman’s body and women who are living with LNMS are generally warned that symptoms of ataxia may worsen or even develop for the first time during pregnancy. Pregnant women with LNMS should be followed closely by obstetricians that are well trained in dealing with high-risk pregnancies.Patients living with LNMS experience alterations to the shape of their teeth. Taurodontism is generally noted at the dental office at the time of first x-rays. Extra care may be needed in brushing and cleaning all aspects of the affected teeth, and dentists may need special tools to examine all aspects of the affected teeth.
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