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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 -
International Journal of Molecular... Oct 2023The impact of segmental duplications on human evolution and disease is only just starting to unfold, thanks to advancements in sequencing technologies that allow for...
The impact of segmental duplications on human evolution and disease is only just starting to unfold, thanks to advancements in sequencing technologies that allow for their discovery and precise genotyping. The 15q11-q13 locus is a hotspot of recurrent copy number variation associated with Prader-Willi/Angelman syndromes, developmental delay, autism, and epilepsy and is mediated by complex segmental duplications, many of which arose recently during evolution. To gain insight into the instability of this region, we characterized its architecture in human and nonhuman primates, reconstructing the evolutionary history of five different inversions that rearranged the region in different species primarily by accumulation of segmental duplications. Comparative analysis of human and nonhuman primate duplication structures suggests a human-specific gain of directly oriented duplications in the regions flanking the cores and segmental duplications, representing potential genomic drivers for the human-specific expansions. The increasing complexity of segmental duplication organization over the course of evolution underlies its association with human susceptibility to recurrent disease-associated rearrangements.
Topics: Animals; Humans; DNA Copy Number Variations; Primates; Prader-Willi Syndrome; Segmental Duplications, Genomic; Autistic Disorder; Chromosomes, Human, Pair 15; Gene Duplication
PubMed: 37958807
DOI: 10.3390/ijms242115818 -
Orphanet Journal of Rare Diseases Jun 2023Angelman syndrome (AS) is a rare, heterogenous neurogenetic condition, which significantly impacts the lives of people with AS and their families. Valid and reliable...
BACKGROUND
Angelman syndrome (AS) is a rare, heterogenous neurogenetic condition, which significantly impacts the lives of people with AS and their families. Valid and reliable measures reporting key symptoms and functional impairments of AS are required to support development of patient-centered therapies. We describe the development of clinician- and caregiver-reported, AS-specific Global Impression scales for incorporation into clinical trials. Best practice US Food and Drug Administration guidance for measure development was followed with input from expert clinicians, patient advocates, and caregivers during content generation and refinement.
RESULTS
Initial measurement domains for the Symptoms of AS-Clinician Global Impression (SAS-CGI) and the Caregiver-reported AS Scale (CASS) were identified from a conceptual disease model of AS symptoms and impacts, derived from interviews with caregivers and clinicians. Two rounds of cognitive debriefing (CD) interviews were performed; clinicians debriefed the SAS-CGI, with patient advocates and caregivers debriefing the CASS to ensure relevance and comprehension. Feedback was used to refine items and ensure wording was age-appropriate and captured AS-specific symptoms, as well as associated impacts and functional impairments. The SAS-CGI and CASS capture global assessments of seizures, sleep, maladaptive behaviors, expressive communication, fine and gross motor skills, cognition, and self-care, which were determined by clinicians, patient advocates, and caregivers to be the most challenging aspects of AS. Additionally, the measures include items for assessing overall AS symptoms and the meaningfulness of any change. In addition to ratings for severity, impact, and change, a notes field was included in the SAS-CGI to provide the rationale for the chosen rating. CD interviews confirmed the measures covered key concepts of AS from the perspective of clinicians and caregivers, and demonstrated that the measures' instructions, items, and response options were clear and appropriate. Interview feedback informed adjustments to the wording of the instructions and the items.
CONCLUSIONS
The SAS-CGI and CASS were designed to capture multiple AS symptoms, reflecting the heterogeneity and complexity of AS in children 1 to 12 years old. These clinical outcome assessments have been incorporated into AS clinical studies, which will allow for the evaluation of their psychometric properties and inform further refinements if needed.
Topics: Child; Humans; Infant; Child, Preschool; Caregivers; Angelman Syndrome; Surveys and Questionnaires; Patient-Centered Care
PubMed: 37349793
DOI: 10.1186/s13023-023-02729-y -
ELife Jan 2023encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by the antisense transcript (). This leaves neurons...
encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by the antisense transcript (). This leaves neurons susceptible to loss-of-function of maternal . Indeed, Angelman syndrome, a severe neurodevelopmental disorder, is caused by maternal deficiency. A promising therapeutic approach to treating Angelman syndrome is to reactivate the intact paternal by suppressing . Prior studies show that many neurological phenotypes of maternal knockout mice can only be rescued by reinstating expression in early development, indicating a restricted therapeutic window for Angelman syndrome. Here, we report that reducing by antisense oligonucleotides in juvenile or adult maternal knockout mice rescues the abnormal electroencephalogram (EEG) rhythms and sleep disturbance, two prominent clinical features of Angelman syndrome. Importantly, the degree of phenotypic improvement correlates with the increase of Ube3a protein levels. These results indicate that the therapeutic window of genetic therapies for Angelman syndrome is broader than previously thought, and EEG power spectrum and sleep architecture should be used to evaluate the clinical efficacy of therapies.
Topics: Mice; Animals; Angelman Syndrome; Brain; Oligonucleotides, Antisense; Mice, Knockout; Sleep; Ubiquitin-Protein Ligases; Disease Models, Animal
PubMed: 36594817
DOI: 10.7554/eLife.81892 -
Virus Research Oct 2023The Ubiquitin-protein ligase E3A, UBE3A, also known as E6-associated protein (E6-AP), is known to play an essential role in regulating the degradation of various... (Review)
Review
The Ubiquitin-protein ligase E3A, UBE3A, also known as E6-associated protein (E6-AP), is known to play an essential role in regulating the degradation of various proteins by transferring Ub from E2 Ub conjugating enzymes to the substrate proteins. Several studies indicate that UBE3A regulates the stabilities of key viral proteins in the virus-infected cells and, thereby, the infected virus-mediated diseases, even if it were reported that UBE3A participates in non-viral-related human diseases. Furthermore, mutations such as deletions and duplications in the maternally inherited gene in the brain cause human neurodevelopmental disorders such as Angelman syndrome (AS) and autism. It is also known that UBE3A functions as a transcriptional coactivator for the expression of steroid hormone receptors. These reports establish that UBE3A is distinguished by its multitudinous functions that are paramount to viral pathology and human diseases. This review is focused on molecular mechanisms for such intensive participation of UBE3A in disease formation and virus regulation.
Topics: Humans; Ubiquitin-Protein Ligases; Mutation; Brain; Angelman Syndrome; Virus Diseases
PubMed: 37541588
DOI: 10.1016/j.virusres.2023.199191 -
Global Medical Genetics Mar 2021Assisted reproductive technology (ART) is a broad field in infertility that encompasses different types of treatments. These revolutionary treatment methods aimed to aid... (Review)
Review
Assisted reproductive technology (ART) is a broad field in infertility that encompasses different types of treatments. These revolutionary treatment methods aimed to aid infertile or subfertile couples. Treatment was expanded exponentially, as 1 to 3% of the births worldwide takes place with ART procedures. However, treatment is not flawless. Gametes and embryos are exposed to different chemicals and stress through treatment, which leads to disturbance in proper embryo development and results in prenatal and congenital anomalies. When compared with in-vivo development of gametes and preimplantation embryos in mice, in-vitro conditions during ART treatments have been suggested to disturb the gene expression levels, especially imprinted genes. Therefore, ART has been suggested to be associated with increased incidences of different imprinting disorders such as Beckwith-Wiedemann syndrome, Angelman syndrome, and Silver-Russell syndrome, as proved by different case reports and studies. This literature review aims to explain the association of imprinting disorders with this revolutionary treatment procedure.
PubMed: 33748817
DOI: 10.1055/s-0041-1723085 -
Frontiers in Genetics 2021Establishing or ruling out a molecular diagnosis of Prader-Willi or Angelman syndrome (PWS/AS) presents unique challenges due to the variety of different genetic...
Establishing or ruling out a molecular diagnosis of Prader-Willi or Angelman syndrome (PWS/AS) presents unique challenges due to the variety of different genetic alterations that can lead to these conditions. Point mutations, copy number changes, uniparental isodisomy (i-UPD) 15 of two subclasses (segmental or total isodisomy), uniparental heterodisomy (h-UPD), and defects in the chromosome 15 imprinting center can all cause PWS/AS. Here, we outline a combined approach using whole-exome sequencing (WES) and DNA methylation data with methylation-sensitive multiplex ligation-dependent probe amplification (MLPA) to establish both the disease diagnosis and the mechanism of disease with high sensitivity using current standard of care technology and improved efficiency compared to serial methods. The authors encourage the use of this approach in the clinical setting to confirm and establish the diagnosis and genetic defect which may account for the secondary genetic conditions that may be seen in those with isodisomy 15, impacting surveillance and counseling with more accurate recurrence risks. Other similarly affected individuals due to other gene disorders or cytogenetic anomalies such as Rett syndrome or microdeletions would also be identified with this streamlined approach.
PubMed: 34046054
DOI: 10.3389/fgene.2021.608889 -
Journal of Neurodevelopmental Disorders Mar 2022SATB2-associated syndrome (SAS) is a multisystem neurodevelopmental disorder characterised by intellectual disability, speech delay, and craniofacial anomalies. Although...
BACKGROUND
SATB2-associated syndrome (SAS) is a multisystem neurodevelopmental disorder characterised by intellectual disability, speech delay, and craniofacial anomalies. Although the clinical presentation of SAS is well-delineated, behaviours associated with SAS are less well-defined. Given the varied social profile reported in SAS of a 'jovial' predisposition and autistic behaviours, there may be phenotypic overlap with both Angelman syndrome (AS) and non-syndromal autism. This study aimed to describe behaviours in SAS in relation to chronological age and level of ability and contrast aspects of the behavioural phenotype with AS and non-syndromal autism.
METHODS
Informant report questionnaire measures of behaviour, emotion, and autism characteristics were completed for 81 individuals with SAS (aged 1-36 years; 43 male). Within-group associations were analysed, and categorical data were compared between pre-school (1-5 years), school-age (6-15 years), and adolescent and adult SAS sub-groups (16 years and over). Cross-syndrome subscale and item-level analyses were conducted for 63 individuals with SAS (aged 1-27 years; 31 male), who were matched according to age and level of ability to 63 individuals with AS (aged 2-25 years; 32 male) and 63 individuals with non-syndromal autism (aged 3-26 years; 53 male).
RESULTS
In SAS, higher rates of overactivity were moderately associated with lower self-help ability, and higher general anxiety scores were reported for males compared with females. Cross-syndrome subscale analyses uncovered several significant differences (p < .01), with comparatively low rates of stereotyped behaviour, overactivity, insistence on sameness and positive affect, and comparatively greater interest and pleasure and compulsive behaviour in individuals with SAS. Item-level analyses revealed a distinct profile of repetitive and autistic behaviours.
LIMITATIONS
Developmental analysis was based on a cross-sectional rather than a longitudinal research design, the contribution of pain and sleep to behaviour was not explored, and molecular genetic testing to determine genotype-phenotype behavioural relationships was not possible.
CONCLUSIONS
This study highlights the importance of behavioural comparisons to well-delineated groups and the utility of fine-grained item-level analyses to elucidate aspects of behaviour that might be syndrome related or shared across neurodevelopmental disorders. Future research is needed to further describe the distinctive repetitive and autistic behavioural phenotype in SAS.
Topics: Abnormalities, Multiple; Adolescent; Adult; Child; Child, Preschool; Craniofacial Abnormalities; Cross-Sectional Studies; Female; Humans; Infant; Intellectual Disability; Male; Matrix Attachment Region Binding Proteins; Phenotype; Transcription Factors; Young Adult
PubMed: 35350986
DOI: 10.1186/s11689-022-09426-0 -
Frontiers in Psychiatry 2022This study investigated the mental development of children with Angelman syndrome (AS) in China and evaluated the relationship between neurodevelopment and molecular...
OBJECTIVE
This study investigated the mental development of children with Angelman syndrome (AS) in China and evaluated the relationship between neurodevelopment and molecular subtype, age, epilepsy, and sex using the Chinese version of the Griffith Mental Development Scale (GMDS-C) to provide detailed baseline data regarding neurodevelopment with AS in China.
METHODS
Participants were recruited from the AS Natural History Study. The GMDS-C was used to evaluate all participants' mental age and developmental quotients. The general quotient (GQ) and quotients of five subscales (sports, personal-social, auditory language, eye-hand coordination, and comprehensive performance) were calculated.
RESULTS
A total of 119 children (average age: 42.12 months; range, 7.5-95.5 months) with a genetic diagnosis of AS were enrolled. The median GQ score of the GMDS was 29.6 points (95% confidence interval, 28.6-33.25). The children had relatively good locomotor and personal-social skills but poor language skills. Overall, 89% (106/119) had mental ages younger than 24 months for all five subscales. The non-deletion group (i.e., without deletion in chromosome 15q11-13) had higher GQs and locomotor, personal-social, and performance subscale quotients. The GQ was significantly different among the three age subgroups and significantly correlated with age. Compared with the non-epilepsy group, the epilepsy group had lower GQs and lower quotients for the locomotor, personal-social, speech, language, and eye-hand coordination subscales.
CONCLUSION
Children with AS in China experience severe neurodevelopmental deterioration. In addition to age, molecular subtypes and the onset of seizures may also correlate with these patients' intellectual development. The GMDS-C is an accurate tool that can assess the clinical characteristics of AS. The data of this study can be used as baseline data for clinical trials performed to evaluate drug development or other AS treatment development.
PubMed: 35573374
DOI: 10.3389/fpsyt.2022.886028 -
Genes Apr 2022Our study reviewed abnormalities in spontaneous, as well as event-related, brain activity in syndromes with a known genetic underpinning that are associated with... (Review)
Review
Our study reviewed abnormalities in spontaneous, as well as event-related, brain activity in syndromes with a known genetic underpinning that are associated with autistic symptomatology. Based on behavioral and neurophysiological evidence, we tentatively subdivided the syndromes on primarily hyper-sensitive (Fragile X, Angelman) and hypo-sensitive (Phelan-McDermid, Rett, Tuberous Sclerosis, Neurofibromatosis 1), pointing to the way of segregation of heterogeneous idiopathic ASD, that includes both hyper-sensitive and hypo-sensitive individuals. This segmentation links abnormalities in different genes, such as , and , that are causative to the above-mentioned syndromes and associated with synaptic transmission and cell growth, as well as with translational and transcriptional regulation and with sensory sensitivity. Excitation/inhibition imbalance related to GABAergic signaling, and the interplay of tonic and phasic inhibition in different brain regions might underlie this relationship. However, more research is needed. As most genetic syndromes are very rare, future investigations in this field will benefit from multi-site collaboration with a common protocol for electrophysiological and event-related potential (EEG/ERP) research that should include an investigation into all modalities and stages of sensory processing, as well as potential biomarkers of GABAergic signaling (such as 40-Hz ASSR).
Topics: Autistic Disorder; Brain; Fragile X Mental Retardation Protein; Humans; Syndrome
PubMed: 35456477
DOI: 10.3390/genes13040671