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Nature Apr 2021Mutations in the X-linked gene MECP2 cause Rett syndrome, a progressive neurological disorder in which children develop normally for the first one or two years of life...
Mutations in the X-linked gene MECP2 cause Rett syndrome, a progressive neurological disorder in which children develop normally for the first one or two years of life before experiencing profound motor and cognitive decline. At present there are no effective treatments for Rett syndrome, but we hypothesized that using the period of normal development to strengthen motor and memory skills might confer some benefit. Here we find, using a mouse model of Rett syndrome, that intensive training beginning in the presymptomatic period dramatically improves the performance of specific motor and memory tasks, and significantly delays the onset of symptoms. These benefits are not observed when the training begins after symptom onset. Markers of neuronal activity and chemogenetic manipulation reveal that task-specific neurons that are repeatedly activated during training develop more dendritic arbors and have better neurophysiological responses than those in untrained animals, thereby enhancing their functionality and delaying symptom onset. These results provide a rationale for genetic screening of newborns for Rett syndrome, as presymptomatic intervention might mitigate symptoms or delay their onset. Similar strategies should be studied for other childhood neurological disorders.
Topics: Animals; Biomedical Enhancement; Disease Models, Animal; Electrophysiology; Female; Male; Mice; Morris Water Maze Test; Neurons; Prodromal Symptoms; Psychomotor Performance; Rett Syndrome; Rotarod Performance Test; Spatial Learning; Time Factors
PubMed: 33762729
DOI: 10.1038/s41586-021-03369-7 -
Neurobiology of Learning and Memory Nov 2019Rett Syndrome (RTT) is a genetic disorder that is caused by mutations in the x-linked gene coding for methyl-CpG-biding-protein 2 (MECP2) and that mainly affects... (Review)
Review
Rett Syndrome (RTT) is a genetic disorder that is caused by mutations in the x-linked gene coding for methyl-CpG-biding-protein 2 (MECP2) and that mainly affects females. Male and female transgenic mouse models of RTT have been studied extensively, and we have learned a great deal regarding RTT neuropathology and how MeCP2 deficiency may be influencing brain function and maturation. In this manuscript we review what is known concerning structural and coinciding functional and behavioral deficits in RTT and in mouse models of MeCP2 deficiency. We also introduce our own corroborating data regarding behavioral phenotype and morphological alterations in volume of the cortex and striatum and the density of neurons, aberrations in experience-dependent plasticity within the barrel cortex and the impact of MeCP2 loss on glial structure. We conclude that regional structural changes in genetic models of RTT show great similarity to the alterations in brain structure of patients with RTT. These region-specific modifications often coincide with phenotype onset and contribute to larger issues of circuit connectivity, progression, and severity. Although the alterations seen in mouse models of RTT appear to be primarily due to cell-autonomous effects, there are also non-cell autonomous mechanisms including those caused by MeCP2-deficient glia that negatively impact healthy neuronal function. Collectively, this body of work has provided a solid foundation on which to continue to build our understanding of the role of MeCP2 on neuronal and glial structure and function, its greater impact on neural development, and potential new therapeutic avenues.
Topics: Animals; Basal Ganglia; Brain; Disease Models, Animal; Hippocampus; Humans; Methyl-CpG-Binding Protein 2; Mice; Motor Disorders; Neuronal Plasticity; Rett Syndrome
PubMed: 30502397
DOI: 10.1016/j.nlm.2018.11.007 -
Molecular Psychiatry Apr 2010Neuroimmunology was once referred to in terms of its pathological connotation only and was generally understood as covering the deleterious involvement of the immune... (Review)
Review
Neuroimmunology was once referred to in terms of its pathological connotation only and was generally understood as covering the deleterious involvement of the immune system in various diseases and disorders of the central nervous system (CNS). However, our conception of the function of the immune system in the structure, function, and plasticity of the CNS has undergone a sea change after relevant discoveries over the past two decades, and continues to be challenged by more recent studies of neurodevelopment and cognition. This review summarizes the recent advances in understanding of immune-system participation in the development and functioning of the CNS under physiological conditions. Considering as an example Rett syndrome a devastating neurodevelopmental disease, we offer a hypothesis that might help to explain the part played by immune cells in its etiology, and hence suggests that the immune system might be a feasible therapeutic target for alleviation of some of the symptoms of this and other autism spectrum disorders.
Topics: Animals; Autistic Disorder; Brain Diseases; Humans; Immune System Diseases; Rett Syndrome
PubMed: 20177406
DOI: 10.1038/mp.2010.21 -
Archives of Disease in Childhood May 2006Rett syndrome (RS) is a neurodevelopmental disease,1 affecting approximately 1 in 10 000-15 000 females. Clinical severity of RS may vary with increasing age, following... (Review)
Review
Rett syndrome (RS) is a neurodevelopmental disease,1 affecting approximately 1 in 10 000-15 000 females. Clinical severity of RS may vary with increasing age, following a four stage model.
Topics: Adolescent; Adult; Arrhythmias, Cardiac; Autonomic Nervous System; Child; Echocardiography; Female; Humans; Rett Syndrome
PubMed: 16632674
DOI: 10.1136/adc.2005.090290 -
Orphanet Journal of Rare Diseases Jul 2018Complex neurodevelopmental disorders need multi-disciplinary treatment approaches for optimal care. The clinical effectiveness of treatments is limited in patients with... (Review)
Review
Complex neurodevelopmental disorders need multi-disciplinary treatment approaches for optimal care. The clinical effectiveness of treatments is limited in patients with rare genetic syndromes with multisystem morbidity. Emotional and behavioural dysregulation is common across many neurodevelopmental disorders. It can manifest in children across multiple diagnostic groups, including those on the autism spectrum and in rare genetic syndromes such as Rett Syndrome (RTT). There is, however a remarkable scarcity in the literature on the impact of the autonomic component on emotional and behavioural regulation in these disorders, and on the longer-term outcomes on disorder burden.RTT is a debilitating and often life-threatening disorder involving multiple overlapping physiological systems. Autonomic dysregulation otherwise known as dysautonomia is a cardinal feature of RTT characterised by an imbalance between the sympathetic and parasympathetic arms of the autonomic nervous system. Unlocking the autonomic component of emotional and behavioural dysregulation would be central in reducing the impairment seen in patients with RTT. In this vein, Emotional, Behavioural and Autonomic Dysregulation (EBAD) would be a useful construct to target for treatment which could mitigate burden and improve the quality of life of patients.RTT can be considered as a congenital dysautonomia and because EBAD can give rise to impairments occurring in multiple overlapping physiological systems, understanding these physiological responses arising out of EBAD would be a critical part to consider when planning treatment strategies and improving clinical outcomes in these patients. Biometric guided pharmacological and bio-feedback therapy for the behavioural and emotional aspects of the disorder offers an attracting perspective to manage EBAD in these patients. This can also allow for the stratification of patients into clinical trials and could ultimately help streamline the patient care pathway for optimal outcomes.The objectives of this review are to emphasise the key issues relating to the management of EBAD in patients with RTT, appraise clinical trials done in RTT from the perspective of autonomic physiology and to discuss the potential of EBAD as a target for clinical trials.
Topics: Clinical Trials as Topic; Emotions; Humans; Nervous System Malformations; Quality of Life; Rett Syndrome
PubMed: 30064458
DOI: 10.1186/s13023-018-0873-8 -
The Turkish Journal of Pediatrics 2018Zengin-Akkuş P, Taşkıran EZ, Kabaçam S, Şimşek-Kiper PÖ, Haliloğlu G, Boduroğlu K, Utine GE. Clinical and molecular evaluation of 16 patients with Rett...
Zengin-Akkuş P, Taşkıran EZ, Kabaçam S, Şimşek-Kiper PÖ, Haliloğlu G, Boduroğlu K, Utine GE. Clinical and molecular evaluation of 16 patients with Rett syndrome. Turk J Pediatr 2018; 60: 1-9. Rett syndrome is a neurodevelopmental disorder caused by mutations in MECP2. The disease is characterized by early neurological regression following a normal initial development. The diagnosis is a clinical one, based on major and minor diagnostic criteria. This study, in a group of patients from a single tertiary center, aimed to evaluate the efficiency of clinical diagnosis and to see if there was a diagnostic delay. A second aim was to investigate genotype-phenotype correlations, based on Pineda scores. In this study, sixteen patients with a median age of 6.5 years (2.5-22 years) were included, following molecular confirmation of clinical diagnosis. The median age at the onset of symptoms and the median age at clinical diagnosis was 1.5 years and 2.5 years, respectively, the difference being statistically significant. Considering the Rett syndrome diagnostic criteria, initially regulated in 2002 and revised in 2010, seven and two patients in our group, respectively, did not meet the main criteria. Pineda scores among mutation groups were statistically not different. To conclude, the present study revealed presence of a diagnostic delay. The challenge may be that the patients do not exhibit full-blown clinical picture initially. No genotype-phenotype correlations were detected in clinical severity, as measured by Pineda scores. Moreover, the diagnostic criteria revised in 2010 are more comprehensive as compared to the 2002 criteria; however, further revision may increase diagnostic sensitivity.
Topics: Adolescent; Child; Child, Preschool; Delayed Diagnosis; Female; Genotype; Growth Disorders; Humans; Methyl-CpG-Binding Protein 2; Mutation; Phenotype; Rett Syndrome; Sequence Analysis, DNA; Young Adult
PubMed: 30102473
DOI: 10.24953/turkjped.2018.01.001 -
Genome Medicine Feb 2017Rett syndrome is a profound neurological disorder caused by mutations in the MECP2 gene, but preclinical research has indicated that it is potentially treatable.... (Review)
Review
Rett syndrome is a profound neurological disorder caused by mutations in the MECP2 gene, but preclinical research has indicated that it is potentially treatable. Progress towards this goal depends on the development of increasingly relevant model systems and on our improving knowledge of MeCP2 function in the brain.
Topics: Brain; Female; Humans; Male; Methyl-CpG-Binding Protein 2; Mutation; Rett Syndrome
PubMed: 28212680
DOI: 10.1186/s13073-017-0411-7 -
Neuropharmacology Jan 2014BDNF is the best-characterized neurotrophin in terms of its gene structure and modulation, secretion processing, and signaling cascades following its release. In... (Review)
Review
BDNF is the best-characterized neurotrophin in terms of its gene structure and modulation, secretion processing, and signaling cascades following its release. In addition to diverse features at the genetic and molecular levels, the abundant expression in several regions of the central nervous system has implicated BDNF as a potent modulator in many aspects of neuronal development, as well as synaptic transmission and plasticity. Impairments in any of these critical functions likely contribute to a wide array of neurodevelopmental, neurodegenerative, and neuropsychiatric diseases. In this review, we focus on a prevalent neurodevelopmental disorder, Rett syndrome (RTT), which afflicts 1:15,000 women world-wide. We describe the consequences of loss-of-function mutations in the gene encoding the transcription factor methyl-CpG binding protein 2 (MeCP2) in RTT, and then elaborate on the current understanding of how MeCP2 controls BDNF expression. Finally, we discuss the literature regarding alterations in BDNF levels in RTT individuals and MeCP2-based mouse models, as well as recent progress in searching for rational therapeutic interventions. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.
Topics: Animals; Brain-Derived Neurotrophic Factor; Female; Humans; Methyl-CpG-Binding Protein 2; Mice; Mutation; Rett Syndrome
PubMed: 23597512
DOI: 10.1016/j.neuropharm.2013.03.024 -
Scientific Reports Aug 2022Fragile X syndrome (FXS) and Rett syndrome (RTT) are developmental disorders currently not diagnosed before toddlerhood. Even though speech-language deficits are among...
Fragile X syndrome (FXS) and Rett syndrome (RTT) are developmental disorders currently not diagnosed before toddlerhood. Even though speech-language deficits are among the key symptoms of both conditions, little is known about infant vocalisation acoustics for an automatic earlier identification of affected individuals. To bridge this gap, we applied intelligent audio analysis methodology to a compact dataset of 4454 home-recorded vocalisations of 3 individuals with FXS and 3 individuals with RTT aged 6 to 11 months, as well as 6 age- and gender-matched typically developing controls (TD). On the basis of a standardised set of 88 acoustic features, we trained linear kernel support vector machines to evaluate the feasibility of automatic classification of (a) FXS vs TD, (b) RTT vs TD, (c) atypical development (FXS+RTT) vs TD, and (d) FXS vs RTT vs TD. In paradigms (a)-(c), all infants were correctly classified; in paradigm (d), 9 of 12 were so. Spectral/cepstral and energy-related features were most relevant for classification across all paradigms. Despite the small sample size, this study reveals new insights into early vocalisation characteristics in FXS and RTT, and provides technical underpinnings for a future earlier identification of affected individuals, enabling earlier intervention and family counselling.
Topics: Acoustics; Fragile X Syndrome; Humans; Infant; Language; Rett Syndrome
PubMed: 35922535
DOI: 10.1038/s41598-022-17203-1 -
Epidemiology and patient journey of Rett syndrome in the United States: a real-world evidence study.BMC Neurology Apr 2023Rett syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects females and is associated with high clinical burden. However, literature...
BACKGROUND
Rett syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects females and is associated with high clinical burden. However, literature characterizing the real-world journey of patients with RTT is limited. This study provided an overview of the epidemiology, patient characteristics, clinical manifestations, healthcare resource utilization (HRU), costs, and treatment patterns of patients with RTT in the US.
METHODS
IQVIA™ Medical Claims Data and Longitudinal Prescription Data (11/01/2016-10/31/2019) were used to identify female patients with RTT, with the first observed diagnosis defined as the index date. Annual incidence and prevalence of RTT were assessed over the entire study period; clinical manifestations, all-cause and RTT-related HRU and costs, and treatment patterns were evaluated during the observation period-from the index date to end of clinical activity or end of data availability, whichever occurred first. Results were further stratified into pediatric (< 18 years) and adult (≥ 18 years) subgroups.
RESULTS
In 2019, prevalence and incidence of RTT was 0.32 and 0.23 per 10,000 enrollees, respectively. Among 5,940 female patients (pediatric: 3,078; adult: 2,862) with mean observation period of 2.04 years, the most prevalent clinical manifestations were neurological disorders (72.8%), gastrointestinal/nutritional disorders (41.9%), and orthopedic disorders (34.6%). The incidence rate of all-cause HRU was 44.43 visits per-patient-per-year and RTT-related HRU comprised 47% of all-cause HRU. Mean all-cause healthcare costs were $40,326 per-patient-per-year, with medical costs driven by home/hospice care visits, therapeutic services, outpatient visits, and inpatient visits. RTT-related healthcare costs comprised 45% of all-cause healthcare costs. The most prevalent supportive therapy and pharmacologic agent were feeding assistance (37.9%) and antiepileptic drugs (54.8%), respectively. Trends were similar by subgroup; although, rates of HRU were generally higher among pediatric patients relative to adult patients (all-cause: 52.43 and 35.86, respectively), which translated into higher mean healthcare costs (all-cause: $45,718 and $34,548, respectively).
CONCLUSIONS
Patients with RTT have substantial disease burden, including prevalent clinical manifestations, high rates of HRU and annual healthcare costs, and reliance on pharmacologic and supportive therapies. These findings underscore the unmet need for effective therapies to target the multifactorial manifestations of RTT.
Topics: Adult; Humans; Female; Child; United States; Rett Syndrome; Retrospective Studies; Health Resources; Health Care Costs; Patient Acceptance of Health Care
PubMed: 37016355
DOI: 10.1186/s12883-023-03181-y