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Jonathan Kipnis - One of the best experts on this subject based on the ideXlab platform.
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wild type microglia arrest pathology in a mouse model of Rett Syndrome
Nature, 2012Co-Authors: Noel C Derecki, James C Cronk, Zhenjie Lu, Eric Xu, Stephen B G Abbott, Patrice G Guyenet, Jonathan KipnisAbstract:Transplanting bone marrow from wild-type mice into MECP2-lacking mice results in wild-type microglial engraftment, extends lifespan and reduces symptoms of disease such as breathing and locomotor abnormalities, implicating microglia in the pathophysiology of Rett Syndrome. The X-linked autism spectrum disorder known as Rett Syndrome is predominantly linked to mutations in the MECP2 gene. It is typically associated with neuronal dysfunction, almost exclusively in girls, but new evidence suggests that restoring MECP2 function in other cell types may also arrest disease development. Here, the authors show in a mouse model that transplanting bone marrow from wild-type mice into mice lacking Mecp2 results in an invasion of donor-derived microglial cells into the brain, accompanied by increased lifespan and reduced signs of disease, including improved breathing and locomotion. The donor cells expressed normal MECP2 and high levels of the neurotrophic factor IGF-1. These results point to a crucial role for microglia in Rett Syndrome, and open the possibility that bone-marrow implants might be of therapeutic benefit. Rett Syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein1,2,3,4,5. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction6. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett Syndrome. Transplantation of wild-type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysmcre on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2+/− females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett Syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.
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wild type microglia arrest pathology in a mouse model of Rett Syndrome
Nature, 2012Co-Authors: Noel C Derecki, James C Cronk, Stephen B G Abbott, Patrice G Guyenet, Jonathan KipnisAbstract:Rett Syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett Syndrome. Transplantation of wild-type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2(+/-) females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett Syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.
Alan K Percy - One of the best experts on this subject based on the ideXlab platform.
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multisite study of evoked potentials in Rett Syndrome
Annals of Neurology, 2021Co-Authors: Joni N Saby, Sarika U Peters, Tim A Benke, Shannon M Standridge, Junko Matsuzaki, Clare Cutrifrench, Lindsay C Swanson, David N Lieberman, Alexandra P Key, Alan K PercyAbstract:Objective The aim of the current study was to evaluate the utility of evoked potentials as a biomarker of cortical function in Rett Syndrome (RTT). As a number of disease-modifying therapeutics are currently under development, there is a pressing need for biomarkers to objectively and precisely assess the effectiveness of these treatments. Method Yearly visual evoked potentials (VEPs) and auditory evoked potentials (AEPs) were acquired from individuals with RTT, aged 2 to 37 years, and control participants across 5 sites as part of the Rett Syndrome and Related Disorders Natural History Study. Baseline and year 1 data, when available, were analyzed and the repeatability of the results was tested. Two Syndrome-specific measures from the Natural History Study were used for evaluating the clinical relevance of the VEP and AEP parameters. Results At the baseline study, group level comparisons revealed reduced VEP and AEP amplitude in RTT compared to control participants. Further analyses within the RTT group indicated that this reduction was associated with RTT-related symptoms, with greater severity associated with lower VEP and AEP amplitude. In participants with RTT, VEP and AEP amplitude was also negatively associated with age. Year 1 follow-up data analyses yielded similar findings and evidence of repeatability of EPs at the individual level. Interpretation The present findings indicate the promise of evoked potentials (EPs) as an objective measure of disease severity in individuals with RTT. Our multisite approach demonstrates potential research and clinical applications to provide unbiased assessment of disease staging, prognosis, and response to therapy. ANN NEUROL 2021;89:790-802.
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biliary tract disease in girls and young women with Rett Syndrome
Journal of Pediatric Gastroenterology and Nutrition, 2019Co-Authors: Kathleen J Motil, Jeffrey L Neul, Jane B Lane, Judy O Barrish, Fran Annese, Suzanne Geerts, Lauren Mcnair, Steven A Skinner, Daniel G Glaze, Alan K PercyAbstract:OBJECTIVE We reviewed medical records and conducted a nationwide survey to characterize the clinical features and determine the prevalence of biliary tract disease in girls and women with Rett Syndrome (RTT). METHODS Sixty-two individuals with RTT and biliary tract disease were identified from the membership of Rett Syndrome Organization and patient files of the principal investigator. Medical records of 46 individuals were reviewed for presenting features, diagnostic tests, and treatment outcomes of biliary tract disease. We designed a questionnaire that probed the frequency of risk factors and treatment outcomes of biliary tract disease in RTT. The questionnaire was completed by 271 parents whose daughters met the clinical criteria for RTT and/or had MECP2 mutations and participated in the Natural History of Rett Syndrome Study. RESULTS Presenting symptoms identified by record review included abdominal pain (94%), irritability (88%), weight loss (64%), and vomiting (52%). Biliary dyskinesia, cholecystitis, and cholelithiasis were identified in 90%, 77%, and 70%, respectively, by cholescintigraphy, surgical pathology, and abdominal ultrasound. The prevalence of biliary tract disease was 4.4% (n = 12) in the RTT cohort. Risk factors included older age (P < 0.001) and a positive family history (P < 0.01). Diagnoses included cholecystitis (n = 5), biliary dyskinesia (n = 6), and cholelithiasis (n = 7). Ten individuals underwent surgery; 7 had resolution of symptoms after surgical intervention. CONCLUSIONS Biliary tract disease is not unique to RTT, but may be under-recognized because of the cognitive impairment of affected individuals. Early diagnostic evaluation and intervention may improve the health and quality of life of individuals affected with RTT and biliary tract disease.
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longitudinal course of epilepsy in Rett Syndrome and related disorders
Brain, 2017Co-Authors: Daniel C Tarquinio, Jeffrey L Neul, Kathleen J Motil, Jane B Lane, Steven A Skinner, Alan K Percy, Wei Hou, Anne T Berg, Walter E Kaufmann, Daniel G GlazeAbstract:Epilepsy is common in Rett Syndrome, an X-linked dominant disorder caused by mutations in the MECP2 gene, and in Rett-related disorders, such as MECP2 duplication. However, neither the longitudinal course of epilepsy nor the patterns of seizure onset and remission have been described in Rett Syndrome and related conditions. The present study summarizes the findings of the Rett Syndrome Natural History study. Participants with clinical Rett Syndrome and those with MECP2 mutations without the clinical Syndrome were recruited through the Rett Natural History study from 2006 to 2015. Clinical details were collected, and cumulative lifetime prevalence of epilepsy was determined using the Kaplan-Meier estimator. Risk factors for epilepsy were assessed using Cox proportional hazards models. Of 1205 participants enrolled in the study, 922 had classic Rett Syndrome, and 778 of these were followed longitudinally for 3939 person-years. The diagnosis of atypical Rett Syndrome with a severe clinical phenotype was associated with higher prevalence of epilepsy than those with classic Rett Syndrome. While point prevalence of active seizures ranged from 30% to 44%, the estimated cumulative lifetime prevalence of epilepsy using Kaplan-Meier approached 90%. Specific MECP2 mutations were not significantly associated with either seizure prevalence or seizure severity. In contrast, many clinical features were associated with seizure prevalence; frequency of hospitalizations, inability to walk, bradykinesia, scoliosis, gastrostomy feeding, age of seizure onset, and late age of diagnosis were independently associated with higher odds of an individual having epilepsy. Aggressive behaviour was associated with lower odds. Three distinct patterns of seizure prevalence emerged in classic Rett Syndrome, including those who did not have seizures throughout the study, those who had frequent relapse and remission, and those who had relentless seizures. Although 248 of those with classic Rett Syndrome and a history of seizures were in terminal remission at last contact, only 74 (12% of those with a history of epilepsy) were seizure free and off anti-seizure medication. When studied longitudinally, point prevalence of active seizures is relatively low in Rett Syndrome, although lifetime risk of epilepsy is higher than previously reported. While daily seizures are uncommon in Rett Syndrome, prolonged remission is less common than in other causes of childhood onset epilepsy. Complete remission off anti-seizure medications is possible, but future efforts should be directed at determining what factors predict when withdrawal of medications in those who are seizure free is propitious.
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pathogenesis of lethal cardiac arrhythmias in mecp2 mutant mice implication for therapy in Rett Syndrome
Science Translational Medicine, 2011Co-Authors: Mark D Mccauley, Steven A Skinner, Alan K Percy, Tiannan Wang, Elise Mike, Jose A Herrera, David L Beavers, Tengwei Huang, Christopher S Ward, Daniel G GlazeAbstract:Rett Syndrome is a neurodevelopmental disorder typically caused by mutations in methyl-CpG–binding protein 2 ( MECP2 ) in which 26% of deaths are sudden and of unknown cause. To explore the hypothesis that these deaths may be due to cardiac dysfunction, we characterized the electrocardiograms in 379 people with Rett Syndrome and found that 18.5% show prolongation of the corrected QT interval (QTc), an indication of a repolarization abnormality that can predispose to the development of an unstable fatal cardiac rhythm. Male mice lacking MeCP2 function, Mecp2 Null/Y , also have prolonged QTc and show increased susceptibility to induced ventricular tachycardia. Female heterozygous null mice, Mecp2 Null/+ , show an age-dependent prolongation of QTc associated with ventricular tachycardia and cardiac-related death. Genetic deletion of MeCP2 function in only the nervous system was sufficient to cause long QTc and ventricular tachycardia, implicating neuronally mediated changes to cardiac electrical conduction as a potential cause of ventricular tachycardia in Rett Syndrome. The standard therapy for prolonged QTc in Rett Syndrome, β-adrenergic receptor blockers, did not prevent ventricular tachycardia in Mecp2 Null/Y mice. To determine whether an alternative therapy would be more appropriate, we characterized cardiomyocytes from Mecp2 Null/Y mice and found increased persistent sodium current, which was normalized when cells were treated with the sodium channel–blocking anti-seizure drug phenytoin. Treatment with phenytoin reduced both QTc and sustained ventricular tachycardia in Mecp2 Null/Y mice. These results demonstrate that cardiac abnormalities in Rett Syndrome are secondary to abnormal nervous system control, which leads to increased persistent sodium current. Our findings suggest that treatment in people with Rett Syndrome would be more effective if it targeted the increased persistent sodium current to prevent lethal cardiac arrhythmias.
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epilepsy and the natural history of Rett Syndrome
Neurology, 2010Co-Authors: Daniel G Glaze, Jeffrey L Neul, Kathleen J Motil, Jane B Lane, Judy O Barrish, Fran Annese, Suzanne Geerts, Steven A Skinner, Alan K Percy, Joy GrahamAbstract:Background: Rett Syndrome (RTT) is a neurodevelopmental disorder primarily seen in females, most with a mutation in MECP2 . Epilepsy has been reported in 50%–80%. Previous reports were based on small sample sizes or parent-completed questionnaires, or failed to consider the impact of specific MECP2 mutations. Methods: The Rare Disease Consortium Research Network for RTT is an NIH-funded project to characterize the clinical spectrum and natural history of RTT in advance of clinical trials. Evaluations include clinical status (classic vs atypical RTT), MECP2 mutations, clinical severity, and presence, frequency, and treatment of seizures. Results: Enrollment as of June 2008 is 602; 528 (88%) meet clinical criteria for classic RTT. Of these, 493 (93%) have MECP2 mutations. Age range was 8 months to 64 years. A total of 360 (60%) were reported to have seizures, including 315 (60%) classic and 45 (61%) atypical RTT. Physician assessment of the 602 indicated that 48% had seizures. There was no significant difference in seizure occurrence by race/ethnicity. A significant age impact for seizures was seen and seizures were infrequent before age 2 years. MECP2 mutations most frequently associated with epilepsy were T158M (74%) and R106W (78%), and less frequently R255X and R306C (both 49%). Individuals with seizures had greater overall clinical severity, and greater impairment of ambulation, hand use, and communication. Discussion: Seizures are common in Rett Syndrome, have an age-related onset and occurrence, vary by mutation, and are associated with greater clinical severity. This information represents a key consideration for designing clinical trials.
Noel C Derecki - One of the best experts on this subject based on the ideXlab platform.
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wild type microglia arrest pathology in a mouse model of Rett Syndrome
Nature, 2012Co-Authors: Noel C Derecki, James C Cronk, Zhenjie Lu, Eric Xu, Stephen B G Abbott, Patrice G Guyenet, Jonathan KipnisAbstract:Transplanting bone marrow from wild-type mice into MECP2-lacking mice results in wild-type microglial engraftment, extends lifespan and reduces symptoms of disease such as breathing and locomotor abnormalities, implicating microglia in the pathophysiology of Rett Syndrome. The X-linked autism spectrum disorder known as Rett Syndrome is predominantly linked to mutations in the MECP2 gene. It is typically associated with neuronal dysfunction, almost exclusively in girls, but new evidence suggests that restoring MECP2 function in other cell types may also arrest disease development. Here, the authors show in a mouse model that transplanting bone marrow from wild-type mice into mice lacking Mecp2 results in an invasion of donor-derived microglial cells into the brain, accompanied by increased lifespan and reduced signs of disease, including improved breathing and locomotion. The donor cells expressed normal MECP2 and high levels of the neurotrophic factor IGF-1. These results point to a crucial role for microglia in Rett Syndrome, and open the possibility that bone-marrow implants might be of therapeutic benefit. Rett Syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein1,2,3,4,5. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction6. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett Syndrome. Transplantation of wild-type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysmcre on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2+/− females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett Syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.
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wild type microglia arrest pathology in a mouse model of Rett Syndrome
Nature, 2012Co-Authors: Noel C Derecki, James C Cronk, Stephen B G Abbott, Patrice G Guyenet, Jonathan KipnisAbstract:Rett Syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett Syndrome. Transplantation of wild-type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2(+/-) females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett Syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.
Aimee F. Luat - One of the best experts on this subject based on the ideXlab platform.
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Elimination of medically intractable epileptic drop attacks following endoscopic total corpus callosotomy in Rett Syndrome.
Childs Nervous System, 2017Co-Authors: Keisuke Ueda, Sandeep Sood, Eishi Asano, Ajay Kumar, Aimee F. LuatAbstract:Introduction Rett Syndrome is a neurodevelopmental genetic disorder, characterized by developmental delay, hand stereotypies, abnormal gait, and acquired microcephaly. Epilepsy is very common in Rett Syndrome and can be medically intractable. It remains uncertain if a patient with epileptic drop attacks associated with this genetic disease can benefit from corpus callosotomy.
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elimination of medically intractable epileptic drop attacks following endoscopic total corpus callosotomy in Rett Syndrome
Childs Nervous System, 2017Co-Authors: Sandeep Sood, Eishi Asano, Aimee F. Luat, Ajay Kumar, Keisuke UedaAbstract:Rett Syndrome is a neurodevelopmental genetic disorder, characterized by developmental delay, hand stereotypies, abnormal gait, and acquired microcephaly. Epilepsy is very common in Rett Syndrome and can be medically intractable. It remains uncertain if a patient with epileptic drop attacks associated with this genetic disease can benefit from corpus callosotomy. We report an 8-year-old girl with Rett Syndrome and medically intractable epileptic drop attacks who underwent endoscopic total corpus callosotomy without any complications that led to the successful elimination of her seizures. Total corpus callosotomy is a feasible treatment option for medically intractable epileptic drop attacks in Rett Syndrome and should not be considered as a contraindication in this condition. This is the first reported case of corpus callosotomy in Rett Syndrome.
Daniel G Glaze - One of the best experts on this subject based on the ideXlab platform.
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biliary tract disease in girls and young women with Rett Syndrome
Journal of Pediatric Gastroenterology and Nutrition, 2019Co-Authors: Kathleen J Motil, Jeffrey L Neul, Jane B Lane, Judy O Barrish, Fran Annese, Suzanne Geerts, Lauren Mcnair, Steven A Skinner, Daniel G Glaze, Alan K PercyAbstract:OBJECTIVE We reviewed medical records and conducted a nationwide survey to characterize the clinical features and determine the prevalence of biliary tract disease in girls and women with Rett Syndrome (RTT). METHODS Sixty-two individuals with RTT and biliary tract disease were identified from the membership of Rett Syndrome Organization and patient files of the principal investigator. Medical records of 46 individuals were reviewed for presenting features, diagnostic tests, and treatment outcomes of biliary tract disease. We designed a questionnaire that probed the frequency of risk factors and treatment outcomes of biliary tract disease in RTT. The questionnaire was completed by 271 parents whose daughters met the clinical criteria for RTT and/or had MECP2 mutations and participated in the Natural History of Rett Syndrome Study. RESULTS Presenting symptoms identified by record review included abdominal pain (94%), irritability (88%), weight loss (64%), and vomiting (52%). Biliary dyskinesia, cholecystitis, and cholelithiasis were identified in 90%, 77%, and 70%, respectively, by cholescintigraphy, surgical pathology, and abdominal ultrasound. The prevalence of biliary tract disease was 4.4% (n = 12) in the RTT cohort. Risk factors included older age (P < 0.001) and a positive family history (P < 0.01). Diagnoses included cholecystitis (n = 5), biliary dyskinesia (n = 6), and cholelithiasis (n = 7). Ten individuals underwent surgery; 7 had resolution of symptoms after surgical intervention. CONCLUSIONS Biliary tract disease is not unique to RTT, but may be under-recognized because of the cognitive impairment of affected individuals. Early diagnostic evaluation and intervention may improve the health and quality of life of individuals affected with RTT and biliary tract disease.
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longitudinal course of epilepsy in Rett Syndrome and related disorders
Brain, 2017Co-Authors: Daniel C Tarquinio, Jeffrey L Neul, Kathleen J Motil, Jane B Lane, Steven A Skinner, Alan K Percy, Wei Hou, Anne T Berg, Walter E Kaufmann, Daniel G GlazeAbstract:Epilepsy is common in Rett Syndrome, an X-linked dominant disorder caused by mutations in the MECP2 gene, and in Rett-related disorders, such as MECP2 duplication. However, neither the longitudinal course of epilepsy nor the patterns of seizure onset and remission have been described in Rett Syndrome and related conditions. The present study summarizes the findings of the Rett Syndrome Natural History study. Participants with clinical Rett Syndrome and those with MECP2 mutations without the clinical Syndrome were recruited through the Rett Natural History study from 2006 to 2015. Clinical details were collected, and cumulative lifetime prevalence of epilepsy was determined using the Kaplan-Meier estimator. Risk factors for epilepsy were assessed using Cox proportional hazards models. Of 1205 participants enrolled in the study, 922 had classic Rett Syndrome, and 778 of these were followed longitudinally for 3939 person-years. The diagnosis of atypical Rett Syndrome with a severe clinical phenotype was associated with higher prevalence of epilepsy than those with classic Rett Syndrome. While point prevalence of active seizures ranged from 30% to 44%, the estimated cumulative lifetime prevalence of epilepsy using Kaplan-Meier approached 90%. Specific MECP2 mutations were not significantly associated with either seizure prevalence or seizure severity. In contrast, many clinical features were associated with seizure prevalence; frequency of hospitalizations, inability to walk, bradykinesia, scoliosis, gastrostomy feeding, age of seizure onset, and late age of diagnosis were independently associated with higher odds of an individual having epilepsy. Aggressive behaviour was associated with lower odds. Three distinct patterns of seizure prevalence emerged in classic Rett Syndrome, including those who did not have seizures throughout the study, those who had frequent relapse and remission, and those who had relentless seizures. Although 248 of those with classic Rett Syndrome and a history of seizures were in terminal remission at last contact, only 74 (12% of those with a history of epilepsy) were seizure free and off anti-seizure medication. When studied longitudinally, point prevalence of active seizures is relatively low in Rett Syndrome, although lifetime risk of epilepsy is higher than previously reported. While daily seizures are uncommon in Rett Syndrome, prolonged remission is less common than in other causes of childhood onset epilepsy. Complete remission off anti-seizure medications is possible, but future efforts should be directed at determining what factors predict when withdrawal of medications in those who are seizure free is propitious.
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pathogenesis of lethal cardiac arrhythmias in mecp2 mutant mice implication for therapy in Rett Syndrome
Science Translational Medicine, 2011Co-Authors: Mark D Mccauley, Steven A Skinner, Alan K Percy, Tiannan Wang, Elise Mike, Jose A Herrera, David L Beavers, Tengwei Huang, Christopher S Ward, Daniel G GlazeAbstract:Rett Syndrome is a neurodevelopmental disorder typically caused by mutations in methyl-CpG–binding protein 2 ( MECP2 ) in which 26% of deaths are sudden and of unknown cause. To explore the hypothesis that these deaths may be due to cardiac dysfunction, we characterized the electrocardiograms in 379 people with Rett Syndrome and found that 18.5% show prolongation of the corrected QT interval (QTc), an indication of a repolarization abnormality that can predispose to the development of an unstable fatal cardiac rhythm. Male mice lacking MeCP2 function, Mecp2 Null/Y , also have prolonged QTc and show increased susceptibility to induced ventricular tachycardia. Female heterozygous null mice, Mecp2 Null/+ , show an age-dependent prolongation of QTc associated with ventricular tachycardia and cardiac-related death. Genetic deletion of MeCP2 function in only the nervous system was sufficient to cause long QTc and ventricular tachycardia, implicating neuronally mediated changes to cardiac electrical conduction as a potential cause of ventricular tachycardia in Rett Syndrome. The standard therapy for prolonged QTc in Rett Syndrome, β-adrenergic receptor blockers, did not prevent ventricular tachycardia in Mecp2 Null/Y mice. To determine whether an alternative therapy would be more appropriate, we characterized cardiomyocytes from Mecp2 Null/Y mice and found increased persistent sodium current, which was normalized when cells were treated with the sodium channel–blocking anti-seizure drug phenytoin. Treatment with phenytoin reduced both QTc and sustained ventricular tachycardia in Mecp2 Null/Y mice. These results demonstrate that cardiac abnormalities in Rett Syndrome are secondary to abnormal nervous system control, which leads to increased persistent sodium current. Our findings suggest that treatment in people with Rett Syndrome would be more effective if it targeted the increased persistent sodium current to prevent lethal cardiac arrhythmias.
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epilepsy and the natural history of Rett Syndrome
Neurology, 2010Co-Authors: Daniel G Glaze, Jeffrey L Neul, Kathleen J Motil, Jane B Lane, Judy O Barrish, Fran Annese, Suzanne Geerts, Steven A Skinner, Alan K Percy, Joy GrahamAbstract:Background: Rett Syndrome (RTT) is a neurodevelopmental disorder primarily seen in females, most with a mutation in MECP2 . Epilepsy has been reported in 50%–80%. Previous reports were based on small sample sizes or parent-completed questionnaires, or failed to consider the impact of specific MECP2 mutations. Methods: The Rare Disease Consortium Research Network for RTT is an NIH-funded project to characterize the clinical spectrum and natural history of RTT in advance of clinical trials. Evaluations include clinical status (classic vs atypical RTT), MECP2 mutations, clinical severity, and presence, frequency, and treatment of seizures. Results: Enrollment as of June 2008 is 602; 528 (88%) meet clinical criteria for classic RTT. Of these, 493 (93%) have MECP2 mutations. Age range was 8 months to 64 years. A total of 360 (60%) were reported to have seizures, including 315 (60%) classic and 45 (61%) atypical RTT. Physician assessment of the 602 indicated that 48% had seizures. There was no significant difference in seizure occurrence by race/ethnicity. A significant age impact for seizures was seen and seizures were infrequent before age 2 years. MECP2 mutations most frequently associated with epilepsy were T158M (74%) and R106W (78%), and less frequently R255X and R306C (both 49%). Individuals with seizures had greater overall clinical severity, and greater impairment of ambulation, hand use, and communication. Discussion: Seizures are common in Rett Syndrome, have an age-related onset and occurrence, vary by mutation, and are associated with greater clinical severity. This information represents a key consideration for designing clinical trials.
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Rett Syndrome controlled study of an oral opiate antagonist naltrexone
Annals of Neurology, 1994Co-Authors: Alan K Percy, Daniel G Glaze, Rebecca J Schultz, Huda Y Zoghbi, Daniel Williamson, James D Frost, Joseph Jankovic, Deborah J Del Junco, Martha L Skender, S C WaringAbstract:HYPOTHESIS: The opiate antagonist, naltrexone, will be beneficial in Rett Syndrome. SUBJECTS: Twenty-five individuals fulfilling the criteria for Rett Syndrome. METHOD: Randomized, double-blind, placebo-controlled crossover trial with two treatment periods, 4 months each, and an intervening 1-month washout period. Clinical stage, motor and cognitive development, motor-behavioral analysis, neurophysiological parameters (computerized electroencephalographic analysis, breathing characteristics, quantification of stereotyped hand movements, and sleep characteristics), and cerebrospinal fluid beta-endorphin measurements were evaluated at baseline and at the end of each treatment period. RESULTS: Only data from the first period of this study were analyzed due to significant sequence effects in the crossover design. This analysis indicated positive effects on certain respiratory characteristics including decreased disorganized breathing during wakefulness. Four (40%) of the individuals receiving naltrexone progressed one or more clinical stages versus none of the individuals receiving placebo. The adjusted (for baseline value and Rett stage) end of treatment psychomotor test age (Bayley Scales) was significantly higher for the placebo group. There was no significant change for the other parameters. CONCLUSION: Naltrexone may modify some of the respiratory disturbance in Rett Syndrome. Declines in motor function and more rapid progression of the disorder suggest a deleterious effect.
