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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 -
Frontiers in Molecular Neuroscience 2023Recent studies promote new interest in the intersectionality between autism spectrum disorder (ASD) and Alzheimer's Disease. We have reported high levels of Amyloid-β... (Review)
Review
Recent studies promote new interest in the intersectionality between autism spectrum disorder (ASD) and Alzheimer's Disease. We have reported high levels of Amyloid-β Precursor Protein (APP) and secreted APP-alpha (sAPP) and low levels of amyloid-beta (Aβ) peptides 1-40 and 1-42 (Aβ40, Aβ42) in plasma and brain tissue from children with ASD. A higher incidence of microcephaly (head circumference less than the 3 percentile) associates with ASD compared to head size in individuals with typical development. The role of Aβ peptides as contributors to acquired microcephaly in ASD is proposed. Aβ may lead to microcephaly via disruption of neurogenesis, elongation of the G1/S cell cycle, and arrested cell cycle promoting apoptosis. As the APP gene exists on Chromosome 21, excess Aβ peptides occur in Trisomy 21-T21 (Down's Syndrome). Microcephaly and some forms of ASD associate with T21, and therefore potential mechanisms underlying these associations will be examined in this review. Aβ peptides' role in other neurodevelopmental disorders that feature ASD and acquired microcephaly are reviewed, including dup 15q11.2-q13, Angelman and Rett syndrome.
PubMed: 37808474
DOI: 10.3389/fnmol.2023.1201723 -
Frontiers in Neuroscience 2024Critical phases of neurodevelopment and gut microbiota diversification occur in early life and both processes are impacted by genetic and environmental factors. Recent...
Functional contribution of the intestinal microbiome in autism spectrum disorder, attention deficit hyperactivity disorder, and Rett syndrome: a systematic review of pediatric and adult studies.
INTRODUCTION
Critical phases of neurodevelopment and gut microbiota diversification occur in early life and both processes are impacted by genetic and environmental factors. Recent studies have shown the presence of gut microbiota alterations in neurodevelopmental disorders. Here we performed a systematic review of alterations of the intestinal microbiota composition and function in pediatric and adult patients affected by autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and Rett syndrome (RETT).
METHODS
We searched selected keywords in the online databases of PubMed, Cochrane, and OVID (January 1980 to December 2021) with secondary review of references of eligible articles. Two reviewers independently performed critical appraisals on the included articles using the Critical Appraisal Skills Program for each study design.
RESULTS
Our systematic review identified 18, 7, and 3 original articles describing intestinal microbiota profiles in ASD, ADHD, and RETT, respectively. Decreased Firmicutes and increased Bacteroidetes were observed in the gut microbiota of individuals affected by ASD and ADHD. Proinflammatory cytokines, short-chain fatty acids and neurotransmitter levels were altered in ASD and RETT. Constipation and visceral pain were related to changes in the gut microbiota in patients affected by ASD and RETT. Hyperactivity and impulsivity were negatively correlated with (phylum Firmicutes) and positively correlated with sp. (phylum Bacteroidetes) in ADHD subjects. Five studies explored microbiota-or diet-targeted interventions in ASD and ADHD. Probiotic treatments with sp. and fecal microbiota transplantation from healthy donors reduced constipation and ameliorated ASD symptoms in affected children. Perinatal administration of sp. prevented the onset of Asperger and ADHD symptoms in adolescence. Micronutrient supplementation improved disease symptomatology in ADHD without causing significant changes in microbiota communities' composition.
DISCUSSION
Several discrepancies were found among the included studies, primarily due to sample size, variations in dietary practices, and a high prevalence of functional gastrointestinal symptoms. Further studies employing longitudinal study designs, larger sample sizes and multi-omics technologies are warranted to identify the functional contribution of the intestinal microbiota in developmental trajectories of the human brain and neurobehavior.
SYSTEMATIC REVIEW REGISTRATION
https://clinicaltrials.gov/, CRD42020158734.
PubMed: 38516317
DOI: 10.3389/fnins.2024.1341656 -
Cellular and Molecular Life Sciences :... Nov 2023AMPA receptors are members of the glutamate receptor family and mediate a fast component of excitatory synaptic transmission at virtually all central synapses. Thus,...
AMPA receptors are members of the glutamate receptor family and mediate a fast component of excitatory synaptic transmission at virtually all central synapses. Thus, their functional characteristics are a critical determinant of brain function. We evaluate intolerance of each GRIA gene to genetic variation using 3DMTR and report here the functional consequences of 52 missense variants in GRIA1-4 identified in patients with various neurological disorders. These variants produce changes in agonist EC, response time course, desensitization, and/or receptor surface expression. We predict that these functional and localization changes will have important consequences for circuit function, and therefore likely contribute to the patients' clinical phenotype. We evaluated the sensitivity of variant receptors to AMPAR-selective modulators including FDA-approved drugs to explore potential targeted therapeutic options.
Topics: Humans; Nervous System Diseases; Synaptic Transmission; Receptors, AMPA; Synapses
PubMed: 37921875
DOI: 10.1007/s00018-023-04991-6 -
Neurological Sciences : Official... May 2024Rett syndrome (RTT) is an uncommon inherited neurodevelopmental disorder that affects brain development, mostly in females. It results from mutation in MECP2 gene in the... (Review)
Review
BACKGROUND
Rett syndrome (RTT) is an uncommon inherited neurodevelopmental disorder that affects brain development, mostly in females. It results from mutation in MECP2 gene in the long arm (q) of the X chromosome.
OBJECTIVE
Trofinetide is a recently developed drug that has a neuroprotective effect on neurons, and it is our aim in this meta-analysis to evaluate its efficacy and safety in treating Rett syndrome patients.
METHODS
We searched 5 databases (PubMed, Scopus, Embase, Web of Science, and Cochrane Library databases) to identify randomized controlled trials (RCTs) comparing Trofinetide and placebo in patients with Rett syndrome until August 13, 2023.Our primary outcomes were the Clinical Global Impression-Improvement (CGI) and the Rett syndrome Behavior Questionnaire (RSBQ). We used Risk of Bias Assessment tool-2 (ROB2) to assess the methodological quality of the included randomized controlled trials.
RESULTS
Three RCTs with a total of 325 patients were included with a follow-up duration ranging from one month to three months. 186 patients received the intervention drug (Trofinetide) and 138 received the placebo. Trofinetide was found to reduce CGI and RSBQ significantly more than placebo (MD = -0.35, 95% CI [-0.52 to -0.18], P 0.0001), (MD = -3.40, 95% CI [-3.69 to -3.12], P 0.00001) respectively. Most adverse events did not show any statistical difference between Trofinetide and the placebo.
CONCLUSION
Trofinetide offers promise as a potential effective and safe therapeutic opportunity for a population without many available treatments, with improvements seen on both CGI and RSBQ assessments and no severe adverse effects reported.
PubMed: 38771525
DOI: 10.1007/s10072-024-07584-8 -
Neuron Jun 2024Mutations in the methyl-DNA-binding protein MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). How MECP2 contributes to transcriptional regulation in...
Mutations in the methyl-DNA-binding protein MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). How MECP2 contributes to transcriptional regulation in normal and disease states is unresolved; it has been reported to be an activator and a repressor. We describe here the first integrated CUT&Tag, transcriptome, and proteome analyses using human neurons with wild-type (WT) and mutant MECP2 molecules. MECP2 occupies CpG-rich promoter-proximal regions in over four thousand genes in human neurons, including a plethora of autism risk genes, together with RNA polymerase II (RNA Pol II). MECP2 directly interacts with RNA Pol II, and genes occupied by both proteins showed reduced expression in neurons with MECP2 patient mutations. We conclude that MECP2 acts as a positive cofactor for RNA Pol II gene expression at many neuronal genes that harbor CpG islands in promoter-proximal regions and that RTT is due, in part, to the loss of gene activity of these genes in neurons.
Topics: RNA Polymerase II; Methyl-CpG-Binding Protein 2; Humans; Neurons; Transcription, Genetic; Promoter Regions, Genetic; Rett Syndrome; CpG Islands; Mutation; Gene Expression Regulation
PubMed: 38697112
DOI: 10.1016/j.neuron.2024.04.007 -
Epilepsia Open Feb 2024We aim to assess the efficacy and tolerance of cannabidiol as adjunctive therapy for Rett syndrome (RTT) patients with epilepsy. We conducted a longitudinal... (Observational Study)
Observational Study
We aim to assess the efficacy and tolerance of cannabidiol as adjunctive therapy for Rett syndrome (RTT) patients with epilepsy. We conducted a longitudinal observational study through a monocentric cohort of 46 patients with RTT. Patients were recruited from March 2020 to October 2022 and were treated with Epidyolex® (cannabidiol, CBD, 100 mg/mL oral solution). In our cohort, 26 patients had associated epilepsy (26/46 [56%]), and 10/26 (38%) were treated with CBD, in combination with clobazam in 50% of cases. The median dose at their last follow-up was 15 mg/kg/day. The median treatment duration was 13 months (range: 1-32 months). CBD reduced the incidence of seizures in seven out of 10 patients (70%) with one seizure-free patient, two patients with a reduction of seizures of more than 75%, and four patients with a decrease of more than 50%. No aggravation of symptoms or adverse effects were observed. Only one patient experienced a transitory drooling and somnolence episode at the CBD initiation. Half of the patients showed a reduction in agitation and/or anxiety attacks, and an improvement in spasticity was reported in 4/10 (40%) of patients. CBD appears to have potential therapeutic value for the treatment of drug-resistant epilepsy in Rett syndrome. CBD is well tolerated and, when used in combination with clobazam, may increase the effectiveness of clobazam alone.
Topics: Humans; Cannabidiol; Clobazam; Anticonvulsants; Rett Syndrome; Epilepsy; Seizures
PubMed: 37485779
DOI: 10.1002/epi4.12796 -
Journal of Translational Medicine Oct 2023Rett syndrome is a neuropediatric disease occurring due to mutations in MECP2 and characterized by a regression in the neuronal development following a normal postnatal...
BACKGROUND
Rett syndrome is a neuropediatric disease occurring due to mutations in MECP2 and characterized by a regression in the neuronal development following a normal postnatal growth, which results in the loss of acquired capabilities such as speech or purposeful usage of hands. While altered neurotransmission and brain development are the center of its pathophysiology, alterations in mitochondrial performance have been previously outlined, shaping it as an attractive target for the disease treatment.
METHODS
We have thoroughly described mitochondrial performance in two Rett models, patients' primary fibroblasts and female Mecp2 mice brain, discriminating between different brain areas. The characterization was made according to their bioenergetics function, oxidative stress, network dynamics or ultrastructure. Building on that, we have studied the effect of leriglitazone, a PPARγ agonist, in the modulation of mitochondrial performance. For that, we treated Rett female mice with 75 mg/kg/day leriglitazone from weaning until sacrifice at 7 months, studying both the mitochondrial performance changes and their consequences on the mice phenotype. Finally, we studied its effect on neuroinflammation based on the presence of reactive glia by immunohistochemistry and through a cytokine panel.
RESULTS
We have described mitochondrial alterations in Rett fibroblasts regarding both shape and bioenergetic functions, as they displayed less interconnected and shorter mitochondria and reduced ATP production along with increased oxidative stress. The bioenergetic alterations were recalled in Rett mice models, being especially significant in cerebellum, already detectable in pre-symptomatic stages. Treatment with leriglitazone recovered the bioenergetic alterations both in Rett fibroblasts and female mice and exerted an anti-inflammatory effect in the latest, resulting in the amelioration of the mice phenotype both in general condition and exploratory activity.
CONCLUSIONS
Our studies confirm the mitochondrial dysfunction in Rett syndrome, setting the differences through brain areas and disease stages. Its modulation through leriglitazone is a potential treatment for this disorder, along with other diseases with mitochondrial involvement. This work constitutes the preclinical necessary evidence to lead to a clinical trial.
Topics: Humans; Female; Mice; Animals; Rett Syndrome; Mitochondria; Brain; Oxidative Stress; Disease Models, Animal
PubMed: 37884937
DOI: 10.1186/s12967-023-04622-5 -
European Journal of Paediatric... Nov 2023To develop a Spanish version of the Rett Syndrome Motor Evaluation Scale (RESMES) for the locomotor function of Rett Syndrome (RTT) using a transcultural methodology.
OBJECTIVE
To develop a Spanish version of the Rett Syndrome Motor Evaluation Scale (RESMES) for the locomotor function of Rett Syndrome (RTT) using a transcultural methodology.
METHODS
The RESMES was cross-culturally adaptated and validated in the Spanish language (RESMES-sp). This study was divided into two well-differentiated phases: 1) a cross-cultural translation and adaptation; 2) psychometric characteristics analysis of the RESMES-sp (reliability, test-retest, construct validity, criteria validity, error measurements). For criteria validity, PAINAD questionnaire, the scoliosis values and PedsQL™, were used.
RESULTS
A total of 63 girls and women diagnosed with RTT participated in this validation study. The total value of the RESMES-sp correlates significantly with all its dimensions, with the correlation value oscillating between 0.645 and 0.939. The correlation value with PAINAD ranges between 0.439 and 0.805; the scoliosis values ranges between 0.245 and 0.564; with PedsQOL™ questionnaire, the correlation values range between 0.273 and 0.663 for the PedsQL™ dimensions, and between 0.447 and 0.648 for the total value of PedsQOL™ questionnaire. The reliability values of Crombach's alpha ranged between 0.897 and 0.998 for the intra-observer analyses and between 0.904 and 0.998 for the inter-observer reliability. The SEM showed a value of 2,829, while the MDC90 showed a value of 6601. The Exploratory Factor Analysis showed 6 factors and values of variance of 86.163%.
CONCLUSIONS
The Spanish version of the RESMES is a reliable and valid tool for the functional assessment and follow-up of patients with RTT.
Topics: Humans; Female; Cross-Cultural Comparison; Rett Syndrome; Scoliosis; Reproducibility of Results; Surveys and Questionnaires; Psychometrics
PubMed: 37788534
DOI: 10.1016/j.ejpn.2023.09.008 -
Frontiers in Immunology 2023The association between gut microbiota and central nervous system (CNS) development has garnered significant research attention in recent years. Evidence suggests... (Review)
Review
The association between gut microbiota and central nervous system (CNS) development has garnered significant research attention in recent years. Evidence suggests bidirectional communication between the CNS and gut microbiota through the brain-gut axis. As a long and complex process, CNS development is highly susceptible to both endogenous and exogenous factors. The gut microbiota impacts the CNS by regulating neurogenesis, myelination, glial cell function, synaptic pruning, and blood-brain barrier permeability, with implication in various CNS disorders. This review outlines the relationship between gut microbiota and stages of CNS development (prenatal and postnatal), emphasizing the integral role of gut microbes. Furthermore, the review explores the implications of gut microbiota in neurodevelopmental disorders, such as autism spectrum disorder, Rett syndrome, and Angelman syndrome, offering insights into early detection, prompt intervention, and innovative treatments.
Topics: Humans; Gastrointestinal Microbiome; Autism Spectrum Disorder; Central Nervous System Diseases; Central Nervous System
PubMed: 38343438
DOI: 10.3389/fimmu.2023.1288256