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Journal of Neurochemistry Jan 2021The Kölliker-Fuse nucleus (KF) is a functionally distinct component of the parabrachial complex, located in the dorsolateral pons of mammals. The KF has a major role in... (Review)
Review
The Kölliker-Fuse nucleus (KF) is a functionally distinct component of the parabrachial complex, located in the dorsolateral pons of mammals. The KF has a major role in respiration and upper airway control. A comprehensive understanding of the KF and its contributions to respiratory function and dysfunction requires an appreciation for its neurochemical characteristics. The goal of this review is to summarize the diverse neurochemical composition of the KF, focusing on the neurotransmitters, neuromodulators, and neuropeptides present. We also include a description of the receptors expressed on KF neurons and transporters involved in each system, as well as their putative roles in respiratory physiology. Finally, we provide a short section reviewing the literature regarding neurochemical changes in the KF in the context of respiratory dysfunction observed in SIDS and Rett syndrome. By over-viewing the current literature on the neurochemical composition of the KF, this review will serve to aid a wide range of topics in the future research into the neural control of respiration in health and disease.
Topics: Animals; Humans; Kolliker-Fuse Nucleus; Respiration
PubMed: 32396650
DOI: 10.1111/jnc.15041 -
Diagnostics (Basel, Switzerland) Nov 2023Rett syndrome (RTT) is a neurodevelopmental disorder marked by profound cognitive, communication, and motor impairments. Despite identified genotype/phenotype...
Rett syndrome (RTT) is a neurodevelopmental disorder marked by profound cognitive, communication, and motor impairments. Despite identified genotype/phenotype connections, the extent of clinical severity varies even among individuals sharing the same genetic mutation. Diverse sociocultural environments, such as the level of inclusivity of the scholar system, the time spent with family, and the intensity of the rehabilitative intervention provided, might influence their development diversely. This study examines the severity of RTT in people in Italy and Israel, countries with distinct contradictory approaches to caring for those with intricate disabilities, across two age groups. Data from 136 Italian and 59 Israeli girls and women with RTT were assessed and divided into two age categories: above and below 12 years. The RARS, a standardized RTT-specific clinical severity tool, was administered. Despite no differences in age and genetic characteristics, the Italian group showed better scores in the RARS motor and disease-related characteristics areas in both age groups. Moreover, the young Italian participants gathered better total RARS scores and emotional and behavioral characteristics area scores. Furthermore, the young group showed significantly less scoliosis, foot problems, and epilepsy than the older group. These findings endorse the inclusion of girls with RTT in the regular schooling system for a limited daily period, investing in high activity levels within the home and community environments, and suggest continuously providing the person with daily occasions of physical activity and socialization.
PubMed: 37958286
DOI: 10.3390/diagnostics13213390 -
Frontiers in Cell and Developmental... 2022Neuroinflammation is a cause of neurodevelopmental disorders such as autism spectrum disorders, fetal alcohol syndrome, and cerebral palsy. Converging lines of evidence... (Review)
Review
Neuroinflammation is a cause of neurodevelopmental disorders such as autism spectrum disorders, fetal alcohol syndrome, and cerebral palsy. Converging lines of evidence from basic and clinical sciences suggest that dysregulation of the epigenetic landscape, including DNA methylation and miRNA expression, is associated with neuroinflammation. Genetic and environmental factors can affect the interaction between epigenetics and neuroinflammation, which may cause neurodevelopmental disorders. In this minireview, we focus on neuroinflammation that might be mediated by epigenetic dysregulation in microglia, and compare studies using mammals and zebrafish.
PubMed: 35646933
DOI: 10.3389/fcell.2022.852752 -
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 -
Journal of Neurodevelopmental Disorders May 2022Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common,...
BACKGROUND
Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT.
METHODS
Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019.
RESULTS
Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P < 0.001), older age (P < 0.001), and mild MECP2 variants (P = 0.002).
CONCLUSION
Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care.
TRIAL REGISTRATION
NCT00299312 and NCT02738281.
Topics: Anti-Anxiety Agents; Anxiety; Female; Humans; Rett Syndrome
PubMed: 35568815
DOI: 10.1186/s11689-022-09432-2 -
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 -
Frontiers in Genetics 2021MeCP2 protein, encoded by the gene, binds to DNA and affects transcription. Outside of this activity the true range of MeCP2 function is still not entirely clear. As... (Review)
Review
MeCP2 protein, encoded by the gene, binds to DNA and affects transcription. Outside of this activity the true range of MeCP2 function is still not entirely clear. As gene mutations cause the neurodevelopmental disorder Rett syndrome in 1 in 10,000 female births, much of what is known about the biologic function of MeCP2 comes from studying human cell culture models and rodent models with gene mutations. In this review, the full scope of MeCP2 research available in the NIH Pubmed (https://pubmed.ncbi.nlm.nih.gov/) data base to date is considered. While not all original research can be mentioned due to space limitations, the main aspects of MeCP2 and Rett syndrome research are discussed while highlighting the work of individual researchers and research groups. First, the primary functions of MeCP2 relevant to Rett syndrome are summarized and explored. Second, the conflicting evidence and controversies surrounding emerging aspects of MeCP2 biology are examined. Next, the most obvious gaps in MeCP2 research studies are noted. Finally, the most recent discoveries in MeCP2 and Rett syndrome research are explored with a focus on the potential and pitfalls of novel treatments and therapies.
PubMed: 33968128
DOI: 10.3389/fgene.2021.624290 -
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 -
BMJ Paediatrics Open 2020Rett syndrome (RTT) is a severe, progressive neurodevelopmental disorder with multisystem comorbidities that evolve across a patient's lifespan requiring attentive... (Review)
Review
BACKGROUND
Rett syndrome (RTT) is a severe, progressive neurodevelopmental disorder with multisystem comorbidities that evolve across a patient's lifespan requiring attentive coordination of subspecialty care by primary care providers. A comprehensive, up-to-date synthesis of medical comorbidities in RTT would aid care coordination and anticipatory guidance efforts by healthcare providers. Our objective was to review and summarise published evidence regarding prevalence of RTT medical comorbidities across all relevant organ systems.
METHODS
Search of PubMed from January 2000 to July 2019 was performed using the search terms (Rett and AND patient) OR (Rett and AND cohort). Articles reporting the prevalence of clinical findings in RTT were assessed with respect to the size and nature of the cohorts interrogated and their relevance to clinical care.
RESULTS
After review of over 800 records, the multisystem comorbidities of RTT were summarised quantitatively from 18 records comprising both retrospective and prospective cohorts (31-983 subjects). Neurological comorbidities had the highest prevalence, occurring in nearly all individuals with gastrointestinal and orthopaedic concerns almost as prevalent as neurological. With the exception of low bone mineral content which was relatively common, endocrine comorbidities were seen in only around one-third of patients. Although more prevalent compared with the general population, cardiac conduction abnormalities were the least common comorbidity in RTT.
CONCLUSIONS
Effective care coordination for RTT requires knowledge of and attention to multiple comorbidities across multiple unrelated organ systems. Many issues common to RTT can potentially be managed by a primary care provider but the need for sub-specialist referral can be anticipated. Since the median life expectancy extends into the sixth decade with evolving subspecialty requirements throughout this time, paediatric providers may be tasked with continued coordination of these comorbidities or transitioning to adult medicine and specialists with experience managing individuals with complex medical needs.
PubMed: 33024833
DOI: 10.1136/bmjpo-2020-000731 -
Metabolites Oct 2019Rett syndrome is a severe neurodevelopmental disorder affecting mostly females and is caused by loss-of-function mutations in the gene that encoded the...
Rett syndrome is a severe neurodevelopmental disorder affecting mostly females and is caused by loss-of-function mutations in the gene that encoded the methyl-CpG-binding protein 2. The pathogenetic mechanisms of Rett syndrome are not completely understood and metabolic derangements are emerging as features of Rett syndrome. We performed a semi-quantitative tandem mass spectrometry-based analysis that measured over 900 metabolites on blood samples from 14 female subjects with Rett syndrome carrying mutations. The metabolic profiling revealed alterations in lipids, mostly involved in sphingolipid metabolism, and sphinganine/sphingosine, that are known to have a neurotrophic role. Further investigations are required to understand the mechanisms underlying such perturbations and their significance in the disease pathogenesis. Nevertheless, these metabolites are attractive for studies on the disease pathogenesis and as potential disease biomarkers.
PubMed: 31658741
DOI: 10.3390/metabo9100221