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Scientific Reports Jan 2021Individuals with Rett syndrome (RTT) commonly demonstrate Parkinsonian features and dystonia at teen age; however, the pathological reason remains unclear. Abnormal iron...
Individuals with Rett syndrome (RTT) commonly demonstrate Parkinsonian features and dystonia at teen age; however, the pathological reason remains unclear. Abnormal iron accumulation in deep gray matter were reported in some Parkinsonian-related disorders. In this study, we investigated the iron accumulation in deep gray matter of RTT and its correlation with dystonia severity. We recruited 18 RTT-diagnosed participants with MECP2 mutations, from age 4 to 28, and 28 age-gender matched controls and investigated the iron accumulation by susceptibility weighted image (SWI) in substantia nigra (SN), globus pallidus (GP), putamen, caudate nucleus, and thalamus. Pearson's correlation was applied for the relation between iron accumulation and dystonia severity. In RTT, the severity of dystonia scales showed significant increase in subjects older than 10 years, and the contrast ratios of SWI also showed significant differences in putamen, caudate nucleus and the average values of SN, putamen, and GP between RTT and controls. The age demonstrated moderate to high negative correlations with contrast ratios. The dystonia scales were correlated with the average contrast ratio of SN, putamen and GP, indicating iron accumulation in dopaminergic system and related grey matter. As the first SWI study for RTT individuals, we found increased iron deposition in dopaminergic system and related grey matter, which may partly explain the gradually increased dystonia.
Topics: Adolescent; Adult; Brain Mapping; Case-Control Studies; Child; Child, Preschool; Dystonic Disorders; Female; Gray Matter; Humans; Iron; Iron Overload; Magnetic Resonance Imaging; Methyl-CpG-Binding Protein 2; Mutation; Rett Syndrome; Severity of Illness Index; Young Adult
PubMed: 33436916
DOI: 10.1038/s41598-020-80723-1 -
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 -
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 -
Neurobiology of Learning and Memory Nov 2019Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), a progressive X-linked neurological disorder characterized by loss of developmental... (Review)
Review
Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), a progressive X-linked neurological disorder characterized by loss of developmental milestones, intellectual disability and breathing abnormality. Despite being a monogenic disorder, the pathogenic mechanisms by which mutations in MeCP2 impair neuronal function and underlie the RTT symptoms have been challenging to elucidate. The seemingly simple genetic root and the availability of genetic data from RTT patients have led to the generation and characterization of a series of mouse models recapitulating RTT-associated genetic mutations. This review focuses on the studies of RTT mouse models and describe newly obtained pathogenic insights from these studies. We also highlight the potential of studying pathophysiology using genetics-based modeling approaches in rodents and suggest a future direction to tackle the pathophysiology of intellectual disability with known or complex genetic causes.
Topics: Animals; Disease Models, Animal; Humans; Intellectual Disability; Mice; Rett Syndrome
PubMed: 30447288
DOI: 10.1016/j.nlm.2018.11.006 -
Developmental Medicine and Child... Aug 2020To summarize existing interventions and their outcomes in Rett syndrome (RTT) rehabilitation and identify gaps in the literature. (Review)
Review
AIM
To summarize existing interventions and their outcomes in Rett syndrome (RTT) rehabilitation and identify gaps in the literature.
METHOD
Five databases (Ovid MEDLINE, Ovid Embase Classic, Ovid PsycINFO, EBSCO CINAHL Plus, and ProQuest ERIC) were systematically searched up to 23rd July 2018 for studies describing rehabilitation interventions. Data on study participants, design, and outcomes were extracted.
RESULTS
Sixty-two articles were included in the final review. Evidence consistently demonstrated that females with RTT can improve their gross motor, fine motor, and communicative skills with rehabilitation. All 11 interventions targeting gross motor function, namely ambulation, achieved functional improvements. Twenty of 24 articles describing fine motor rehabilitation studies succeeded in decreasing stereotypies, improving functional hand use, and/or reducing self-injurious behaviors. Twenty-one of 22 studies describing communication interventions succeeded in training choice-making, communicative language, or socialization behavior. Other key findings include the positive interplay between physical and communicative rehabilitation outcomes, and the ability of females with RTT to improve their cognitive abilities during intervention.
INTERPRETATION
Rehabilitation can impact the daily lives of females with RTT and their caregivers in clinically meaningful ways.
Topics: Humans; Quality of Life; Recovery of Function; Rett Syndrome; Treatment Outcome
PubMed: 32472972
DOI: 10.1111/dmcn.14565 -
Animal Models and Experimental Medicine Dec 2022Rett syndrome (RTT) is a progressive neurodevelopmental disorder that occurs mainly in girls with a range of typical symptoms of autism spectrum disorders. MeCP2 protein... (Review)
Review
Rett syndrome (RTT) is a progressive neurodevelopmental disorder that occurs mainly in girls with a range of typical symptoms of autism spectrum disorders. MeCP2 protein loss-of-function in neural lineage cells is the main cause of RTT pathogenicity. As it is still hard to understand the mechanism of RTT on the basis of only clinical patients or animal models, cell models cultured in vitro play indispensable roles. Here we reviewed the research progress in the pathogenesis of RTT at the cellular level, summarized the preclinical-research-related applications, and prospected potential future development.
Topics: Animals; Rett Syndrome; Methyl-CpG-Binding Protein 2; Neurons; Autism Spectrum Disorder; Disease Models, Animal
PubMed: 35785421
DOI: 10.1002/ame2.12236 -
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 -
Archives of Biochemistry and Biophysics Mar 2021Rett Syndrome (RTT) is a rare neurodevelopmental disorder caused in the 95% of cases by mutations in the X-linked MECP2 gene, affecting almost exclusively females. While...
Rett Syndrome (RTT) is a rare neurodevelopmental disorder caused in the 95% of cases by mutations in the X-linked MECP2 gene, affecting almost exclusively females. While the genetic basis of RTT is known, the exact pathogenic mechanisms that lead to the broad spectrum of symptoms still remain enigmatic. Alterations in the redox homeostasis have been proposed among the contributing factors to the development and progression of the syndrome. Mitochondria appears to play a central role in RTT oxidative damage and a plethora of mitochondrial defects has already been recognized. However, mitochondrial dynamics and mitophagy, which represent critical pathways in regulating mitochondrial quality control (QC), have not yet been investigated in RTT. The present work showed that RTT fibroblasts have networks of hyperfused mitochondria with morphological abnormalities and increased mitochondrial volume. Moreover, analysis of mitophagic flux revealed an impaired PINK1/Parkin-mediated mitochondrial removal associated with an increase of mitochondrial fusion proteins Mitofusins 1 and 2 (MFN1 and 2) and a decrease of fission mediators including Dynamin related protein 1 (DRP1) and Mitochondrial fission 1 protein (FIS1). Finally, challenging RTT fibroblasts with FCCP and 2,4-DNP did not trigger a proper apoptotic cell death due to a defective caspase 3/7 activation. Altogether, our findings shed light on new aspects of mitochondrial dysfunction in RTT that are represented by defective mitochondrial QC pathways, also providing new potential targets for a therapeutic intervention aimed at slowing down clinical course and manifestations in the affected patients.
Topics: Adolescent; Adult; Apoptosis; Caspase 3; Caspase 7; Child; Dynamins; Female; Fibroblasts; GTP Phosphohydrolases; Humans; Membrane Proteins; Methyl-CpG-Binding Protein 2; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Proteins; Mitophagy; Oxidation-Reduction; Rett Syndrome
PubMed: 33549528
DOI: 10.1016/j.abb.2021.108790 -
Neuropediatrics Jun 2020Over 80% of individuals suffering from Rett syndrome (RTT) are affected over their life period by sleeping disorders. Little is known about the impact of those on the...
BACKGROUND
Over 80% of individuals suffering from Rett syndrome (RTT) are affected over their life period by sleeping disorders. Little is known about the impact of those on the quality of life and a clinical approach to the treatment of sleep disturbances is lacking.
AIMS
Primary aim was to assess sleep quality in children and adults. Secondary aim was to assess behavioral disorders and their relationship to sleep quality. The medication taken by the subjects was also included.
METHODS
Sleep quality and medication were assessed using the sleeping questionnaire for children with neurological and other complex diseases (SNAKE). Behavioral disorders were assessed by the Rett Syndrome Behavior Questionnaire (RSBQ). Questionnaires were sent to the 700 members of the (Rett Aid) of which 287 were included. Questionnaires were filled out by the primary caregivers.
RESULTS
Sleep quality was rated as very good to good by over 60% of caregivers in contrast to data available in the literature. Behavioral disorders related to regression such as loss of acquired hand skills ( = 0.046) and isolation ( = 0.002) were found to be associated with sleep quality. Melatonin showed a significant association ( = 0.007) with sleep quality.
CONCLUSION
Our study showed sleep dysfunction to be less prevalent in RTT-affected individuals than evidence from past studies has suggested. Nevertheless, this remains a subjective assessment of sleep quality and therefore the need to find objective, disorder-specific parameters that measure sleep quality in RTT patients persists.
Topics: Adolescent; Adult; Behavioral Symptoms; Child; Female; Humans; Male; Pilot Projects; Prospective Studies; Quality of Life; Rett Syndrome; Sleep Wake Disorders; Young Adult
PubMed: 32143222
DOI: 10.1055/s-0040-1701693 -
Neuroscience and Biobehavioral Reviews Dec 2019Rett syndrome (RTT) is a rare neurological disorder primarily affecting females, causing severe cognitive, social, motor and physiological impairments for which no cure... (Review)
Review
Rett syndrome (RTT) is a rare neurological disorder primarily affecting females, causing severe cognitive, social, motor and physiological impairments for which no cure currently exists. RTT clinical diagnosis is based on the peculiar progression of the disease, since patients show an apparently normal initial development with a subsequent sudden regression at around 2 years of age. Accumulating evidences are rising doubts regarding the absence of early impairments, hence questioning the concept of regression. We reviewed the published literature addressing the pre-symptomatic stage of the disease in both patients and animal models with a particular focus on behavioral, physiological and brain abnormalities. The emerging picture delineates subtle, but reliable impairments that precede the onset of overt symptoms whose bases are likely set up already during embryogenesis. Some of the outlined alterations appear transient, suggesting compensatory mechanisms to occur in the course of development. There is urgent need for more systematic developmental analyses able to detect early pathological markers to be used as diagnostic tools and precocious targets of time-specific interventions.
Topics: Child Development; Child, Preschool; Humans; Rett Syndrome
PubMed: 31108160
DOI: 10.1016/j.neubiorev.2019.05.013