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Protein & Cell Oct 2023The gut microbiota has been found to interact with the brain through the microbiota-gut-brain axis, regulating various physiological processes. In recent years, the... (Review)
Review
The gut microbiota has been found to interact with the brain through the microbiota-gut-brain axis, regulating various physiological processes. In recent years, the impacts of the gut microbiota on neurodevelopment through this axis have been increasingly appreciated. The gut microbiota is commonly considered to regulate neurodevelopment through three pathways, the immune pathway, the neuronal pathway, and the endocrine/systemic pathway, with overlaps and crosstalks in between. Accumulating studies have identified the role of the microbiota-gut-brain axis in neurodevelopmental disorders including autism spectrum disorder, attention deficit hyperactivity disorder, and Rett Syndrome. Numerous researchers have examined the physiological and pathophysiological mechanisms influenced by the gut microbiota in neurodevelopmental disorders (NDDs). This review aims to provide a comprehensive overview of advancements in research pertaining to the microbiota-gut-brain axis in NDDs. Furthermore, we analyzed both the current state of research progress and discuss future perspectives in this field.
Topics: Humans; Brain-Gut Axis; Autism Spectrum Disorder; Brain; Gastrointestinal Microbiome; Neurodevelopmental Disorders
PubMed: 37166201
DOI: 10.1093/procel/pwad026 -
Genes Aug 2023Over the last 20 years, the understanding and natural history of Rett syndrome has advanced, but to date no cure has emerged, with multidisciplinary management being... (Review)
Review
Over the last 20 years, the understanding and natural history of Rett syndrome has advanced, but to date no cure has emerged, with multidisciplinary management being symptomatic and supportive. This study provides a comprehensive review of the clinical features, comorbidities and multidisciplinary management of a well-characterized cohort of females with classical Rett syndrome. We aim to improve awareness and understanding of Rett syndrome amongst pediatricians, pediatric subspecialists and allied health professionals to enable early diagnosis and a streamlined enrolment approach for future clinical trials. Rett syndrome, a complex X-linked condition, affecting mainly females, is due to pathogenic variants of the gene in most affected individuals. The Rett syndrome Multidisciplinary Management clinic at The Children's Hospital at Westmead, Sydney, Australia, was established in 2000. This retrospective analysis of individuals who attended the clinic from 2000 to 2020 was performed to identify the incidence and predicted age of onset of Rett syndrome related comorbidities, disease progression and to review management principles. Data collected included age of Rett syndrome diagnosis, genotype, clinical features and medical comorbidities, such as sleep disturbance, seizures, breathing irregularities, scoliosis, mobility, hand stereotypies, hand function, constipation, feeding ability, use of gastrostomy, communication skills, QTc prolongation, anthropometry, and bruxism. Analysis of 103 girls who fulfilled the clinical diagnostic criteria for classical Rett syndrome with a pathogenic variant of the gene showed a median age of diagnosis of 3 years. The most frequent variant was c.502 C>T.
Topics: Female; Humans; Child; Child, Preschool; Male; Rett Syndrome; Retrospective Studies; Scoliosis; Constipation; Seizures
PubMed: 37628658
DOI: 10.3390/genes14081607 -
Medicina Sep 2023Autism is a neurodevelopmental disorder characterized by deficits in social cognition and communication, restricted interests, and stereotyped behaviors. Frequently... (Review)
Review
Autism is a neurodevelopmental disorder characterized by deficits in social cognition and communication, restricted interests, and stereotyped behaviors. Frequently associated with sensory dysfunction, other neurodevelopmental disorders, neuropsychiatric disorders, epilepsy and/or sleep disorders. This condition will accompany people throughout their lives, which will generate various support and treatment needs. Although there are no drugs that modify the core symptoms of autism, various drugs have shown their usefulness in associated conditions. Atypical antipsychotics for hyperactivity, impulsivity, agitation, auto or heteroaggression crises. Serotonin reuptake inhibitors, to decrease anxiety, obsessive-compulsive symptoms, and irritability/agitation. Stimulants and atomoxetine used for hyperactivity, inattention, and impulsivity. Clonidine and guanfacine show some efficacy on hyperactivity and stereotyped behaviors. Buspirone has been used for restrictive behaviors and anxiety. There are drugs in the research phase such as oxytocin, vasopressin and even some developed for specific entities related to autism such as arbaclofen in Fragile X and Trofinetide that has just been approved for use in Rett syndrome. As specific entities and their pathophysiology are identified, it is likely that tailored treatments will be developed for each entity associated with autism..
Topics: Humans; Autistic Disorder; Stereotyped Behavior; Anxiety; Anxiety Disorders; Autism Spectrum Disorder
PubMed: 37714122
DOI: No ID Found -
Molecular Therapy : the Journal of the... Sep 2023The AAV9 gene therapy vector presented in this study is safe in mice and non-human primates and highly efficacious without causing overexpression toxicity, a major...
The AAV9 gene therapy vector presented in this study is safe in mice and non-human primates and highly efficacious without causing overexpression toxicity, a major challenge for clinical translation of Rett syndrome gene therapy vectors to date. Our team designed a new truncated methyl-CpG-binding protein 2 (MECP2) promoter allowing widespread expression of MECP2 in mice and non-human primates after a single injection into the cerebrospinal fluid without causing overexpression symptoms up to 18 months after injection. Additionally, this new vector is highly efficacious at lower doses compared with previous constructs as demonstrated in extensive efficacy studies performed by two independent laboratories in two different Rett syndrome mouse models carrying either a knockout or one of the most frequent human mutations of Mecp2. Overall, data from this multicenter study highlight the efficacy and safety of this gene therapy construct, making it a promising candidate for first-in-human studies to treat Rett syndrome.
Topics: Humans; Mice; Animals; Rett Syndrome; Primates; Genetic Therapy; Mutation
PubMed: 37481701
DOI: 10.1016/j.ymthe.2023.07.013 -
International Journal of Molecular... Sep 2023A remarkable feature of the brain is its sexual dimorphism. Sexual dimorphism in brain structure and function is associated with clinical implications documented... (Review)
Review
A remarkable feature of the brain is its sexual dimorphism. Sexual dimorphism in brain structure and function is associated with clinical implications documented previously in healthy individuals but also in those who suffer from various brain disorders. Sex-based differences concerning some features such as the risk, prevalence, age of onset, and symptomatology have been confirmed in a range of neurological and neuropsychiatric diseases. The mechanisms responsible for the establishment of sex-based differences between men and women are not fully understood. The present paper provides up-to-date data on sex-related dissimilarities observed in brain disorders and highlights the most relevant features that differ between males and females. The topic is very important as the recognition of disparities between the sexes might allow for the identification of therapeutic targets and pharmacological approaches for intractable neurological and neuropsychiatric disorders.
Topics: Humans; Male; Female; Sex Characteristics; Brain; Brain Diseases
PubMed: 37834018
DOI: 10.3390/ijms241914571 -
Genes & Development Oct 2023Mutations in the methyl-DNA binding domain of MECP2 cause Rett syndrome; however, distinct mutations are associated with different severity of the disease. Live-cell... (Review)
Review
Mutations in the methyl-DNA binding domain of MECP2 cause Rett syndrome; however, distinct mutations are associated with different severity of the disease. Live-cell imaging and single-molecule tracking are sensitive methods to quantify the DNA binding affinity and diffusion dynamics of nuclear proteins. In this issue of , Zhou and colleagues (pp. 883-900) used these imaging methods to quantitatively describe the partial loss of DNA binding resulting from a novel pathological mutation with intermediate disease severity. These data demonstrate how single-molecule tracking can advance understanding of the molecular mechanisms connecting mutations with Rett syndrome pathophysiology.
Topics: Humans; Rett Syndrome; Methyl-CpG-Binding Protein 2; DNA; Mutation; Nuclear Proteins; Protein Domains
PubMed: 37914350
DOI: 10.1101/gad.351285.123 -
Free Radical Biology & Medicine Oct 2023Neuroinflammation plays a crucial role in the onset and the progression of several neuropathologies, from neurodegenerative disorders to migraine, from Rett syndrome to... (Review)
Review
Neuroinflammation plays a crucial role in the onset and the progression of several neuropathologies, from neurodegenerative disorders to migraine, from Rett syndrome to post-COVID 19 neurological manifestations. Inflammasomes are cytosolic multiprotein complexes of the innate immune system that fuel inflammation. They have been under study for the last twenty years and more recently their involvement in neuro-related conditions has been of great interest as possible therapeutic target. The role of oxidative stress in inflammasome activation has been described, however the exact way of action of specific endogenous and exogenous oxidants needs to be better clarified. In this review, we provide the current knowledge on the involvement of inflammasome in the main neuropathologies, emphasizing the importance to further clarify the role of oxidative stress in its activation including the role of mitochondria in inflammasome-induced neuroinflammation.
Topics: Humans; Inflammasomes; Neuroinflammatory Diseases; COVID-19; Inflammation; Neurodegenerative Diseases; NLR Family, Pyrin Domain-Containing 3 Protein
PubMed: 37442280
DOI: 10.1016/j.freeradbiomed.2023.07.010 -
Cureus Jul 2023Rett syndrome (RTT) is a neurodevelopmental disorder that is a leading cause of severe cognitive and physical impairment. RTT typically occurs in females, although rare... (Review)
Review
Rett syndrome (RTT) is a neurodevelopmental disorder that is a leading cause of severe cognitive and physical impairment. RTT typically occurs in females, although rare cases of males with the disease exist. Its genetic cause, symptoms, and clinical progression timeline have also become well-documented since its initial discovery. However, a relatively late diagnosis and lack of an available cure signify that our understanding of the disease is incomplete. Innovative research methods and tools are thereby helping to fill gaps in our knowledge of RTT. Specifically, mouse models of RTT, video analysis, and retrospective parental analysis are well-established tools that provide valuable insights into RTT. Moreover, current and anticipated treatment options are improving the quality of life of the RTT patient population. Collectively, these developments are creating optimistic future perspectives for RTT.
PubMed: 37554594
DOI: 10.7759/cureus.41555 -
Experimental Biology and Medicine... Nov 2023Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG binding protein-2 (MeCP2) gene that is characterized by epilepsy,... (Review)
Review
Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG binding protein-2 (MeCP2) gene that is characterized by epilepsy, intellectual disability, autistic features, speech deficits, and sleep and breathing abnormalities. Neurologically, patients with all three disorders display microcephaly, aberrant dendritic morphology, reduced spine density, and an imbalance of excitatory/inhibitory signaling. Loss-of-function mutations in the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1 genes also cause similar behavioral and neurobiological defects and were referred to as congenital or variant Rett syndrome. The relatively recent realization that CDKL5 deficiency disorder (CDD), FOXG1 syndrome, and Rett syndrome are distinct neurodevelopmental disorders with some distinctive features have resulted in separate focus being placed on each disorder with the assumption that distinct molecular mechanisms underlie their pathogenesis. However, given that many of the core symptoms and neurological features are shared, it is likely that the disorders share some critical molecular underpinnings. This review discusses the possibility that deregulation of common molecules in neurons and astrocytes plays a central role in key behavioral and neurological abnormalities in all three disorders. These include KCC2, a chloride transporter, vGlut1, a vesicular glutamate transporter, GluD1, an orphan-glutamate receptor subunit, and PSD-95, a postsynaptic scaffolding protein. We propose that reduced expression or activity of KCC2, vGlut1, PSD-95, and AKT, along with increased expression of GluD1, is involved in the excitatory/inhibitory that represents a key aspect in all three disorders. In addition, astrocyte-derived brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and inflammatory cytokines likely affect the expression and functioning of these molecules resulting in disease-associated abnormalities.
Topics: Humans; Rett Syndrome; Mutation; Spasms, Infantile; Disks Large Homolog 4 Protein; Symporters
PubMed: 38057990
DOI: 10.1177/15353702231209419