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Current Opinion in Neurobiology Dec 2019Complex adult behaviors arise from the integration of sequential and often overlapping critical periods (CPs) early in life and adolescence. These processes rely on a... (Review)
Review
Complex adult behaviors arise from the integration of sequential and often overlapping critical periods (CPs) early in life and adolescence. These processes rely on a subtle interplay between the set of genes inherited from the parents, the surrounding environment and epigenetic regulation. Methyl-CpG-binding protein 2 (MeCP2) has been shown to recognize epigenetic states and regulate gene expression by reading methylated DNA. Here, we will review the recent findings revealing the role of MeCP2 during postnatal CPs of development using mouse models of Rett (RTT) syndrome.
Topics: Animals; Epigenesis, Genetic; Humans; Methyl-CpG-Binding Protein 2; Mice; Rett Syndrome
PubMed: 31163286
DOI: 10.1016/j.conb.2019.04.004 -
Birth Defects Research Jul 2021In this short review, we provide an overview of developmental disorders causing autonomic nervous system dysregulation. We briefly discuss perinatal conditions that... (Review)
Review
In this short review, we provide an overview of developmental disorders causing autonomic nervous system dysregulation. We briefly discuss perinatal conditions that adversely impact developmental outcomes including apnea of prematurity, sudden infant death syndrome, and Rett syndrome. We provide a brief clinical description, an overview of known or hypothesized mechanisms for the disorder, and current standard of practice for treatment of each condition. Additionally, we consider preventative measures and complications of these disorders to provide further insight into the pathogenesis of specific autonomic dysregulation in neonates. The goal of this short review is to provide an updated understanding of the impact of autonomic dysregulation on development of brainstem circuits and to briefly highlight promising future treatment options and controversies.
Topics: Autonomic Nervous System; Humans; Infant; Infant, Newborn; Rett Syndrome; Sudden Infant Death
PubMed: 33421331
DOI: 10.1002/bdr2.1855 -
Journal of Pediatric and Adolescent... Apr 2021To describe features of menstruation, menstrual-related symptoms, and menstrual management in females with Rett syndrome (RTT) to help develop a clinical approach to...
STUDY OBJECTIVE
To describe features of menstruation, menstrual-related symptoms, and menstrual management in females with Rett syndrome (RTT) to help develop a clinical approach to these parameters in RTT.
DESIGN
Retrospective cross-sectional chart review and prospective survey.
SETTING
Cincinnati Children's Hospital Medical Center, Rett Syndrome and Related Spectrum Disorders Clinic.
PARTICIPANTS
Females with RTT (12-55 years of age) and their caregivers.
MAIN OUTCOME MEASURES
Descriptive data on features of menstruation and menstrual-related symptoms in individuals with Rett syndrome; prevalence, types, reason for use/discontinuation, and efficacy of hormonal treatment in females with RTT.
RESULTS
Age at menarche, menstrual cycle length, and menstrual period length in females with RTT are comparable to those in typically developing females and females with other neurodevelopmental disabilities. Dysmenorrhea and emotional lability are common menstrual cycle-related changes among females with RTT; 22.1% of participants also reported catamenial seizures. Oral progestin, combined oral contraceptive pill, and depot-medroxyprogesterone acetate (DMPA) were effectively used to suppress or regulate menstruation and to manage menstrual-related symptoms.
CONCLUSIONS
Characteristics of menstruation in females with RTT are comparable to those of typically developing females, with the exception of increase in catamenial seizure activity. Hormonal treatments are used for management of menstruation, dysmenorrhea, and seizures. Choice of hormonal treatment is influenced by bone health and immobility in females with RTT.
Topics: Adolescent; Adult; Child; Female; Humans; Middle Aged; Young Adult; Contraceptives, Oral, Combined; Cross-Sectional Studies; Menstruation; Menstruation Disturbances; Ohio; Progestins; Retrospective Studies; Rett Syndrome; Seizures; Surveys and Questionnaires
PubMed: 33186698
DOI: 10.1016/j.jpag.2020.11.002 -
Journal of Medical Genetics Oct 2023Rett syndrome is a genetically caused neurodevelopmental disorder associated with severe impairments and complex comorbidities. This study examined predictors of anxiety... (Observational Study)
Observational Study
BACKGROUND
Rett syndrome is a genetically caused neurodevelopmental disorder associated with severe impairments and complex comorbidities. This study examined predictors of anxiety and depression in Rett syndrome, including genotype.
METHODS
The International Rett Syndrome Database, InterRett, was the data source for this observational study. Associations between genotype, functional abilities, comorbidities, anxiety and depression were estimated with univariate and multivariate regression models. An additional regression model for anxiety included use of an anxiety medication as a predictor variable.
RESULTS
The sample included 210 individuals aged 6-51 years of whom 54 (25.7%) were on psychotropic medication for anxiety or depression. Individuals with the p.Arg294* variant had the highest anxiety scores, as did those with insomnia or excessive daytime sleepiness, irrespective of anxiety medication use. Individuals with the p.Arg306Cys variant had the lowest depression scores, as did those with insomnia or excessive daytime sleepiness.
CONCLUSION
Findings indicated that genotype and sleep have implications for mental health in Rett syndrome, suggesting that anticipatory guidance and proactive management of poor sleep could improve mental health. More research is needed to understand the effects of psychometric medications, which cannot be inferred from this cross-sectional study.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Rett Syndrome; Mental Health; Cross-Sectional Studies; Sleep; Disorders of Excessive Somnolence; Genotype
PubMed: 37055168
DOI: 10.1136/jmg-2022-108905 -
Boletin Medico Del Hospital Infantil de... 2023CDKL5 deficiency syndrome is caused by pathogenic variants in the CDKL5 gene, with a variable clinical spectrum ranging from patients with characteristics of autism...
BACKGROUND
CDKL5 deficiency syndrome is caused by pathogenic variants in the CDKL5 gene, with a variable clinical spectrum ranging from patients with characteristics of autism spectrum disorder to early-onset epilepsy refractory to treatment. Initially, until the gene was discovered, it was considered an atypical form of Rett syndrome. This study aimed to describe the clinical and molecular heterogeneity in CDLK5 disorders among three female patients with CDKL5 pathogenic variants.
CASE REPORTS
We reported three unrelated Mexican female patients evaluated for global developmental delay and epilepsy. All three cases were hemizygotes to a CDKL5 pathogenic variant. In one patient, we performed a 306 gene panel associated with epilepsy. In the other two cases, a human genomic microarray was performed. We describe their clinical features electroencephalogram and brain magnetic resonance evaluations.
CONCLUSIONS
CDKL5 deficiency syndrome represents a challenge for clinicians since the clinical manifestations, electroencephalographic and neuroimaging studies can be non-specific. This syndrome should be suspected in the presence of global developmental delay, autistic behavioral phenotype and epilepsy, associated or not with dysmorphia. Given the similarity between various epileptic encephalopathies, multigene panels including sequencing and duplication/deletion analysis should be requested in which this gene and its possible differential diagnoses are considered, without forgetting the usefulness of genomic techniques in unclear cases.
Topics: Humans; Female; Autism Spectrum Disorder; Spasms, Infantile; Epilepsy; Rett Syndrome
PubMed: 37490689
DOI: 10.24875/BMHIM.22000100 -
Journal of Autism and Developmental... Aug 2020Drug studies on Rett syndrome (RTT) have drastically increased over the past few decades. This review aims to provide master data on bench-to-bedside drug studies... (Review)
Review
Drug studies on Rett syndrome (RTT) have drastically increased over the past few decades. This review aims to provide master data on bench-to-bedside drug studies involving RTT. A comprehensive literature review was performed by searching in PUBMED, MEDLINE and Google Scholar, international, national and regional clinical trial registries and pharmaceutical companies using the keywords "Rett syndrome treatment and/or drug or compound or molecule". Seventy drugs were investigated in non-clinical (N = 65 animal/cell line-based studies; N = 5 iPSC-based study) and clinical trials (N = 34) for ameliorating the symptoms of RTT. Though there is good progress in both clinical and non-clinical studies, none of these drugs entered phase III/IV for being launched as a therapeutic agent for RTT.
Topics: Animals; Disease Models, Animal; Female; Humans; Rett Syndrome
PubMed: 32016693
DOI: 10.1007/s10803-020-04381-y -
Special Care in Dentistry : Official... Nov 2022Intellectual and developmental disabilities are heterogeneous in aetiology and presentation, and one cannot make assumptions about the oral health barriers of those with... (Observational Study)
Observational Study
AIMS
Intellectual and developmental disabilities are heterogeneous in aetiology and presentation, and one cannot make assumptions about the oral health barriers of those with Rett syndrome (RTT) based on findings from generic studies. This study investigated caregivers' perceptions regarding access to dental care for those with (RTT), and associations of dental treatments received by those with RTT with their caregivers' perceived value of oral health and perception of their own as well as their daughter's dental anxiety.
METHODS AND RESULTS
Retrospective observational data of a subset of individuals with confirmed MECP2 mutations in the InterRett database (n = 216) were used to explore caregiver-related factors and their relationships with longitudinal data on dental service utilisation, using negative binomial regression. The main reported barriers to dental care access for individuals with RTT were primarily dentist-related in nature, regardless of dental service history. Those with reported dental nonattendance were of older age. Increasing levels of caregiver-reported dental fear were associated with less frequent dental check-ups or for any appointments for affected individuals.
CONCLUSIONS
Dentist-related barriers and caregiver-reported anxiety may both adversely affect dental attendance for those with RTT. Future research should explore caregivers' beliefs and oral health literacy.
Topics: Humans; Rett Syndrome; Retrospective Studies; Caregivers; Oral Health; Mutation
PubMed: 35290682
DOI: 10.1111/scd.12712 -
Journal of Pediatric Rehabilitation... 2021To perform a scoping review of the evidence for therapeutic interventions to manage functional impairments associated with Rett syndrome (RTT) throughout the lifespan. (Review)
Review
PURPOSE
To perform a scoping review of the evidence for therapeutic interventions to manage functional impairments associated with Rett syndrome (RTT) throughout the lifespan.
METHODS
MEDLINE, EMBASE, PsycINFO, CENTRAL, CINAHL, Scopus and Index to Chiropractic Literature were searched systematically up to December 2019. Two investigators independently reviewed all search results and extracted those that met the inclusion criteria. Human and animal model studies pertaining to therapies that increase functional ability or treat RTT-associated symptoms in all age groups were included. Relevant studies were grouped into intervention categories and rated using the Oxford Centre of Evidence Based Medicine Levels of Evidence. Demographics of participants, interventions, and outcomes were summarized.
RESULTS
Ninety-one articles representing 88 studies met the inclusion criteria, of which 80 were human clinical studies and eight were studies using animal models. Study designs were primarily case series and only six studies involved participants above the age of 40.
CONCLUSION
A small number of rigorously studied rehabilitation interventions have been published. Published studies aim to address a wide variety of functional impairments. Research regarding implementation of therapies for older patients with RTT is lacking and requires further exploration.
Topics: Animals; Humans; Longevity; Rett Syndrome
PubMed: 32894256
DOI: 10.3233/PRM-200683 -
International Journal of Molecular... Feb 2023DNA methylation, one of the most well-studied epigenetic modifications, is involved in a wide spectrum of biological processes. Epigenetic mechanisms control cellular... (Review)
Review
DNA methylation, one of the most well-studied epigenetic modifications, is involved in a wide spectrum of biological processes. Epigenetic mechanisms control cellular morphology and function. Such regulatory mechanisms involve histone modifications, chromatin remodeling, DNA methylation, non-coding regulatory RNA molecules, and RNA modifications. One of the most well-studied epigenetic modifications is DNA methylation that plays key roles in development, health, and disease. Our brain is probably the most complex part of our body, with a high level of DNA methylation. A key protein that binds to different types of methylated DNA in the brain is the methyl-CpG binding protein 2 (MeCP2). MeCP2 acts in a dose-dependent manner and its abnormally high or low expression level, deregulation, and/or genetic mutations lead to neurodevelopmental disorders and aberrant brain function. Recently, some of MeCP2-associated neurodevelopmental disorders have emerged as neurometabolic disorders, suggesting a role for MeCP2 in brain metabolism. Of note, loss-of-function mutation in Rett Syndrome is reported to cause impairment of glucose and cholesterol metabolism in human patients and/or mouse models of disease. The purpose of this review is to outline the metabolic abnormalities in MeCP2-associated neurodevelopmental disorders that currently have no available cure. We aim to provide an updated overview into the role of metabolic defects associated with MeCP2-mediated cellular function for consideration of future therapeutic strategies.
Topics: Animals; Humans; Mice; Brain; DNA Methylation; Epigenesis, Genetic; Methyl-CpG-Binding Protein 2; Rett Syndrome; RNA
PubMed: 36835623
DOI: 10.3390/ijms24044218 -
Molecular Genetics & Genomic Medicine Nov 2019This study aimed to investigate the new genetic etiologies of Rett syndrome (RTT) or Rett-like phenotypes.
BACKGROUND
This study aimed to investigate the new genetic etiologies of Rett syndrome (RTT) or Rett-like phenotypes.
METHODS
Targeted next-generation sequencing (NGS) was performed on 44 Chinese patients with RTT or Rett-like phenotypes, in whom genetic analysis of MECP2, CDKL5, and FOXG1 was negative.
RESULTS
The detection rate was 31.8% (14/44). A de novo pathogenic variant (c.275_276ins AA, p. Cys92*) of KIF1A was identified in a girl with all core features of typical RTT. A patient with atypical RTT was detected having de novo GRIN1 pathogenic variant (c.2337C > A, p. Val793Phe). Additionally, compound heterozygous pathogenic variants of PPT1 gene were detected in a girl, who initially displayed typical RTT features, but progressed into neuronal ceroid lipofuscinoses (NCL) afterwards. Pathogenic variants in KCNQ2, MEF2C, WDR45, TCF4, IQSEC2, and SDHA were also found in our cohort.
CONCLUSIONS
It is the first time that pathogenic variants of GRIN1 and KIF1A were linked to RTT and Rett-like profiles. Our findings expanded the genetic heterogeneity of Chinese RTT or Rett-like patients, and also suggest that some patients with genetic metabolic disease such as NCL, might displayed Rett features initially, and clinical follow-up is essential for the diagnosis.
Topics: Child; Child, Preschool; Female; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Infant; Kinesins; Male; Mutation; Nerve Tissue Proteins; Phenotype; Receptors, N-Methyl-D-Aspartate; Rett Syndrome
PubMed: 31512412
DOI: 10.1002/mgg3.968