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The Journal of Neuroscience : the... Oct 2021Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder characterized by intellectual disabilities, motor and balance deficits, impaired communication, and...
Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder characterized by intellectual disabilities, motor and balance deficits, impaired communication, and a happy, excitable demeanor with frequent laughter. We sought to elucidate a preclinical outcome measure in male and female rats that addressed communication abnormalities of AS and other neurodevelopmental disorders in which communication is atypical and/or lack of speech is a core feature. We discovered, and herein report for the first time, excessive laughter-like 50 kHz ultrasonic emissions in the rat model of AS, which suggests an excitable, playful demeanor and elevated positive affect, similar to the demeanor of individuals with AS. Also in line with the AS phenotype, rats demonstrated aberrant social interactions with a novel partner, distinctive gait abnormalities, impaired cognition, an underlying LTP deficit, and profound reductions in brain volume. These unique, robust phenotypes provide advantages compared with currently available mouse models and will be highly valuable as outcome measures in the evaluation of therapies for AS. Angelman syndrome (AS) is a severe neurogenetic disorder for which there is no cure, despite decades of research using mouse models. This study used a recently developed rat model of AS to delineate disease-relevant outcome measures to facilitate therapeutic development. We found the rat to be a strong model of AS, offering several advantages over mouse models by exhibiting numerous AS-relevant phenotypes, including overabundant laughter-like vocalizations, reduced hippocampal LTP, and volumetric anomalies across the brain. These findings are unconfounded by detrimental motor abilities and background strain, issues plaguing mouse models. This rat model represents an important advancement in the field of AS, and the outcome metrics reported herein will be central to the therapeutic pipeline.
Topics: Angelman Syndrome; Animals; Brain; Disease Models, Animal; Female; Gene Deletion; Laughter; Male; Microcephaly; Organ Culture Techniques; Protein Biosynthesis; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Reflex, Startle; Social Behavior; Ubiquitin-Protein Ligases; Vocalization, Animal
PubMed: 34475199
DOI: 10.1523/JNEUROSCI.0925-21.2021 -
Autism Research : Official Journal of... Jun 2022Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss-of-function mutations in the maternal copy of the UBE3A gene. AS is characterized by intellectual...
Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss-of-function mutations in the maternal copy of the UBE3A gene. AS is characterized by intellectual disability, impaired speech and motor skills, epilepsy, and sleep disruptions. Multiple treatment strategies to re-express functional neuronal UBE3A from the dormant paternal allele were successful in rodent models of AS and have now moved to early phase clinical trials in children. Developing reliable and objective AS biomarkers is essential to guide the design and execution of current and future clinical trials. Our prior work quantified short daytime electroencephalograms (EEGs) to define promising biomarkers for AS. Here, we asked whether overnight sleep is better suited to detect AS EEG biomarkers. We retrospectively analyzed EEGs from 12 overnight sleep studies from individuals with AS with age and sex-matched Down syndrome and neurotypical controls, focusing on low frequency (2-4 Hz) delta rhythms and sleep spindles. Delta EEG rhythms were increased in individuals with AS during all stages of overnight sleep, but overnight sleep did not provide additional benefit over wake in the ability to detect increased delta. Abnormal sleep spindles were not reliably detected in EEGs from individuals with AS during overnight sleep, suggesting that delta rhythms represent a more reliable biomarker. Overall, we conclude that periods of wakefulness are sufficient, and perhaps ideal, to quantify delta EEG rhythms for use as AS biomarkers. LAY SUMMARY: Electroencephalography (EEG) is a safe and reliable way of measuring abnormal brain activity in Angelman syndrome. We found that low-frequency "delta" EEG rhythms are increased in individuals with Angelman syndrome during all stages of overnight sleep. Delta rhythms can be used as a tool to measure improvement in future clinical trials.
Topics: Angelman Syndrome; Autism Spectrum Disorder; Biomarkers; Electroencephalography; Humans; Retrospective Studies; Sleep
PubMed: 35304979
DOI: 10.1002/aur.2709 -
The Journal of Neuroscience : the... Mar 2018Angelman syndrome (AS), a neurodevelopmental disorder associated with intellectual disability, is caused by loss of maternal allele expression of in neurons. Mouse...
Angelman syndrome (AS), a neurodevelopmental disorder associated with intellectual disability, is caused by loss of maternal allele expression of in neurons. Mouse models of AS faithfully recapitulate disease phenotypes across multiple domains, including behavior. Yet in AS, there has been only limited study of behaviors encoded by the prefrontal cortex, a region broadly involved in executive function and cognition. Because cognitive impairment is a core feature of AS, it is critical to develop behavioral readouts of prefrontal circuit function in AS mouse models. One such readout is behavioral extinction, which has been well described mechanistically and relies upon prefrontal circuits in rodents. Here we report exaggerated operant extinction in male AS model mice, concomitant with enhanced excitability in medial prefrontal neurons from male and female AS model mice. Abnormal behavior was specific to operant extinction, as two other prefrontally dependent tasks (cued fear extinction and visuospatial discrimination) were largely normal in AS model mice. Inducible deletion of during adulthood was not sufficient to drive abnormal extinction, supporting the hypothesis that there is an early critical period for development of cognitive phenotypes in AS. This work represents the first formal experimental analysis of prefrontal circuit function in AS, and identifies operant extinction as a useful experimental paradigm for modeling cognitive aspects of AS in mice. Prefrontal cortex encodes "high-level" cognitive processes. Thus, understanding prefrontal function is critical in neurodevelopmental disorders where cognitive impairment is highly penetrant. Angelman syndrome is a neurodevelopmental disorder associated with speech and motor impairments, an outwardly happy demeanor, and intellectual disability. We describe a behavioral phenotype in a mouse model of Angelman syndrome and related abnormalities in prefrontal cortex function. We hypothesize that robust and reliable prefrontally encoded behavior may be used to model cognitive impairments in Angelman syndrome.
Topics: Angelman Syndrome; Animals; Cognition; Cognition Disorders; Conditioning, Operant; Cues; Discrimination, Psychological; Executive Function; Extinction, Psychological; Gene Deletion; Male; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques; Phenotype; Prefrontal Cortex; Ubiquitin-Protein Ligases
PubMed: 29431654
DOI: 10.1523/JNEUROSCI.2828-17.2018 -
Annals of Laboratory Medicine Jan 2022Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genomic imprinting disorders that are mainly caused by a deletion on 15q11-q13, the uniparental disomy of...
BACKGROUND
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genomic imprinting disorders that are mainly caused by a deletion on 15q11-q13, the uniparental disomy of chromosome 15, or an imprinting defect. We evaluated the utility of methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) as a diagnostic tool and for demonstrating the relationship between molecular mechanisms and clinical presentation.
METHODS
We performed MS-MLPA using DNA samples from 93 subjects (45 PWS, 24 AS, and 24 non-PWS/AS controls) who had previously undergone MS-PCR for the diagnosis of PWS/AS. We compared the results of both assays, and patients' clinical phenotypes were reviewed retrospectively.
RESULTS
MS-MLPA showed a 100% concordance rate with MS-PCR. Among the 45 PWS patients, 26 (57.8%) had a deletion of 15q11-q13, and the others (42.2%) had uniparental disomy 15 or an imprinting defect. Among the 24 AS patients, 16 (66.7%) had a deletion of 15q11-q13, 7 AS patients (29.2%) had uniparental disomy 15 or an imprinting defect, and one AS patient (4.2%) showed an imprinting center deletion.
CONCLUSIONS
MS-MLPA has clinical utility for the diagnosis of PWS/AS, and it is superior to MS-PCR in that it can identify the molecular mechanism underlying the disease.
Topics: Angelman Syndrome; Chromosomes, Human, Pair 15; DNA Methylation; Humans; Methylation; Multiplex Polymerase Chain Reaction; Prader-Willi Syndrome; Retrospective Studies
PubMed: 34374352
DOI: 10.3343/alm.2022.42.1.79 -
Sleep Medicine May 2024Angelman Syndrome (AS) is a rare genetic disorder characterised by hyperactivity, overexcitability, developmental delays, and lack of speech.
BACKGROUND
Angelman Syndrome (AS) is a rare genetic disorder characterised by hyperactivity, overexcitability, developmental delays, and lack of speech.
METHODS
This study used secondary data analysis to investigate sleep disturbances in children and adolescents (n = 212) who are enrolled in the Global Angelman Syndrome Registry. Participants were divided into two groups based on the presence or absence of sleep disturbance. The cut-off score of 40 on the Sleep Disturbance Scale for Children was used to indicate the presence or absence of sleep disturbances. Sleep disturbances and their association with co-occurring conditions were examined regarding challenging behaviour, language and communication, infancy history, gastrointestinal symptoms, and epilepsy. Multiple regression was then conducted to investigate possible predictors for sleep disturbances.
RESULTS
Children and adolescents with AS, with and without sleep disturbances, differed considerably regarding anxiety. Sleep disturbances were significantly associated with an ability to use spoken words and computerised communication devices, and anxiety was a predictor of sleep disturbances.
CONCLUSION
Future research is necessary to replicate this novel research, and to advance the clinical treatment of sleep disturbances in children and adolescents with AS.
Topics: Child; Humans; Adolescent; Angelman Syndrome; Sleep Wake Disorders; Epilepsy; Anxiety; Sleep
PubMed: 38479041
DOI: 10.1016/j.sleep.2024.02.038 -
Current Opinion in Endocrinology,... Dec 2010To summarize current evidence in the association of imprinting disorders and assisted reproductive technology. (Review)
Review
PURPOSE OF REVIEW
To summarize current evidence in the association of imprinting disorders and assisted reproductive technology.
RECENT FINDINGS
The worldwide usage of assisted reproductive technology (ART) has continued to increase since the first successful birth of a human after IVF. Since 2002, several reports have raised concerns that children conceived by ART are at increased risk of having imprinting disorders. The majority of published studies have examined DNA methylation in children conceived by ART, but results are conflicting. Beckwith-Wiedemann syndrome and Angelman syndrome are the most extensively studied imprinting disorders and multiple case series and reports have been published on ART-conceived children with these syndromes. Overall the majority of reports suggest that ART might be associated with Beckwith-Wiedermann syndrome and Angelman syndrome, but larger collaborative studies need to be performed.
SUMMARY
The current data suggest an association between imprinting disorders and ART although the absolute risk appears to be low. However, animal studies have established biologic plausibility and there is continuing concern about the possibility of epigenetic changes resulting from ART.
Topics: Angelman Syndrome; Animals; Beckwith-Wiedemann Syndrome; Cellular Reprogramming; Genomic Imprinting; Humans; Reproductive Techniques, Assisted; Risk
PubMed: 20962636
DOI: 10.1097/MED.0b013e32834040a3 -
International Journal of Molecular... Apr 2018Angelman syndrome (AS, MIM 105830) is a rare neurodevelopmental disorder affecting 1:10-20,000 children. Patients show moderate to severe intellectual disability, ataxia...
Angelman syndrome (AS, MIM 105830) is a rare neurodevelopmental disorder affecting 1:10-20,000 children. Patients show moderate to severe intellectual disability, ataxia and absence of speech. Studies on both post-mortem AS human brains and mouse models revealed dysfunctions in the extra synaptic gamma-aminobutyric acid (GABA) receptors implicated in the pathogenesis. Taurine is a free intracellular sulfur-containing amino acid, abundant in brain, considered an inhibiting neurotransmitter with neuroprotective properties. As taurine acts as an agonist of GABA-A receptors, we aimed at investigating whether it might ameliorate AS symptoms. Since mice weaning, we orally administered 1 g/kg/day taurine in water to -deficient mice. To test the improvement of motor and cognitive skills, Rotarod, Novel Object Recognition and Open Field tests were assayed at 7, 14, 21 and 30 weeks, while biochemical tests and amino acid dosages were carried out, respectively, by Western-blot and high-performance liquid chromatography (HPLC) on frozen whole brains. Treatment of mice with taurine significantly improved motor and learning skills and restored the levels of the post-synaptic PSD-95 and pERK1/2-ERK1/2 ratio to wild type values. No side effects of taurine were observed. Our study indicates taurine administration as a potential therapy to ameliorate motor deficits and learning difficulties in AS.
Topics: Angelman Syndrome; Animals; Disease Models, Animal; Female; Learning; Male; Mice; Taurine; gamma-Aminobutyric Acid
PubMed: 29621152
DOI: 10.3390/ijms19041088 -
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 -
Revista de Neurologia Feb 2002In the same way as the genetic basis of disease and developmental disorders with behavioural and intellectual features are being discovered, the opportunity of studying...
INTRODUCTION
In the same way as the genetic basis of disease and developmental disorders with behavioural and intellectual features are being discovered, the opportunity of studying how genes may affect conduct is also developing in both dysfunctional and normal situations.
DEVELOPMENT
The most useful models for studying this problem are the genetic disorders in which the genetic defect has been discovered or is being traced. In parallel with advances in genetics, the behaviour patterns found in each disorder are also being defined and are known as behaviour phenotypes.
CONCLUSIONS
In this article we aim to illustrate information currently available in the field of behaviour phenotypes. The behaviour and intellectual characteristics of the following syndromes are therefore described: fragile X, premutation of the fragile X syndrome, velocardiofacial, Prader Willi, Rett, Angelman and Williams.
Topics: Angelman Syndrome; Behavior; Behavioral Symptoms; Child; Child Behavior Disorders; Female; Fragile X Syndrome; Genetic Diseases, Inborn; Genotype; Humans; Male; Phenotype; Prader-Willi Syndrome; Rett Syndrome; Williams Syndrome
PubMed: 12447788
DOI: No ID Found -
Research in Developmental Disabilities Sep 2022Angelman syndrome (AS), is a rare genetic disorder. This study investigated the relationship between parent-reported comorbid symptoms including gastrointestinal...
Relationships between challenging behavior and gastrointestinal symptoms, sleep problems, and internalizing and externalizing symptoms in children and adolescents with Angelman syndrome.
BACKGROUND
Angelman syndrome (AS), is a rare genetic disorder. This study investigated the relationship between parent-reported comorbid symptoms including gastrointestinal symptoms, sleep problems, internalizing symptoms, and behavior problems in children and adolescents with AS.
METHOD
Parents of 98 children and adolescents with AS completed the Gastrointestinal Symptom Inventory, Children's Sleep Habits Questionnaire, Child Behavior Checklist, Social Communication Questionnaire, and the Behavior Problem Inventory-Short Form. Data were analyzed using descriptive statistics, Pearson's correlation coefficients, and hierarchical multiple regressions.
RESULTS
There was a high frequency of GI symptoms (99%), sleep problems (95.9%), challenging behavior (98%), internalizing symptoms (38%), and 72.4% of children and adolescents presented with ASD symptoms. Self-injurious behavior (SIB), aggressive/destructive behavior, and the frequency of stereotyped behavior positively correlated with GI symptoms and sleep problems and it was moderately negatively associated with age. Internalizing symptoms and age were positively associated with SIB. Aggression was significantly related to gender, but not the presence of ASD symptoms.
CONCLUSIONS
Findings highlight the relationships between comorbid conditions. They may lead to a deeper understanding of how comorbidities present in children and adolescents with Angelman Syndrome.
Topics: Adolescent; Angelman Syndrome; Child; Gastrointestinal Diseases; Humans; Parents; Problem Behavior; Sleep Wake Disorders; Surveys and Questionnaires
PubMed: 35797778
DOI: 10.1016/j.ridd.2022.104293