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Genes Aug 2022Angelman syndrome (AS) is a neurodevelopmental genetic disorder, but there has been limited analysis of a large cohort of Chinese children with Angelman syndrome. This...
Angelman syndrome (AS) is a neurodevelopmental genetic disorder, but there has been limited analysis of a large cohort of Chinese children with Angelman syndrome. This study aims to assess the phenotype and genotype of Chinese children with Angelman syndrome. We retrospectively analyzed data through a detailed online survey combined with an on-site study. Furthermore, phenotype analysis stratified by deletion and non-deletion groups was carried out. The responses of family members of 695 individuals with AS revealed that 577 patients (83.02%) had maternal deletions, 65 patients (9.35%) carried mutations, 31 (4.46%) patients had UPD15pat (one patient with UPD15pat constituted by a mosaic), 10 patients (1.44%) had imprinting defects and 12 (1.58%) patients only showed abnormal methylation without further detection. We identified 50 different pathogenic variants in this cohort, although 18 of these variants were unreported. Recurrent variant c.2507_2510del (p.K836Rfs*4) was found in 7 patients. In the deletion group, patients were diagnosed at an earlier age, had a more severe clinical phenotype, a higher rate of epilepsy with more multiple seizure types, and more frequently combined medication. Strabismus and sleep disturbances were both common in deletion and non-deletion groups. The top three resources invested in caring for AS children are: daily involvement in patient care, rehabilitation cost, and anti-epileptic treatment. Our study showed the genetic composition of Chinese children with 83.02% of maternal deletions, and the mutation spectrum for variants was expanded. Developmental outcomes are associated with genotype, and this was confirmed by deletion patients having a worse clinical phenotype and complex epilepsy.
Topics: Angelman Syndrome; China; Epilepsy; Genotype; Humans; Phenotype; Retrospective Studies
PubMed: 36011358
DOI: 10.3390/genes13081447 -
American Journal of Medical Genetics.... Feb 2015Angelman syndrome (AS) is a neurogenetic disorder. The goal of this study was to investigate the primary health issues affecting adults with AS and to further...
Angelman syndrome (AS) is a neurogenetic disorder. The goal of this study was to investigate the primary health issues affecting adults with AS and to further characterize the natural history and genotype-phenotype correlations. Standardized phone interviews with caregivers for 110 adolescents and adults with AS were conducted. The impact of age, sex, and genotype on specific outcomes in neurology, orthopedics, internal medicine, and psychiatry were investigated. The mean age of individuals with AS was 24 years (range 16-50y). Active seizures were present in 41% of individuals, and 72% had sleep dysfunction. Significant constipation was present in 85%, and 32% were overweight or obese, with obesity disproportionately affecting women. Scoliosis affected 50% with a mean age at diagnosis of 12 years, and 24% of those diagnosed with scoliosis required surgery, an intervention disproportionately affecting men. Sixty-eight percent were able to walk independently, and 13% were able to speak 5 or more words. Self-injurious behavior was exhibited in 52% of individuals. The results of this study indicate that epilepsy severity may assume a bimodal age distribution: seizures are typically most severe in early childhood but may recur in adulthood. While late-adolescent and adult sleep patterns were improved when compared to the degree of sleep dysfunction present during infancy and childhood, the prevalence of poor sleep in adults remained quite high. Primary areas of clinical management identified include the following: seizures, sleep, aspiration risk, GERD, constipation, dental care, vision, obesity, scoliosis, bone density, mobility, communication, behavior, and anxiety.
Topics: Activities of Daily Living; Adolescent; Adult; Angelman Syndrome; Canada; Cohort Studies; Databases, Factual; Female; Humans; Male; Middle Aged; Mutation; Puerto Rico; Ubiquitin-Protein Ligases; Uniparental Disomy; United States; Young Adult
PubMed: 25428759
DOI: 10.1002/ajmg.a.36864 -
Expert Opinion on Therapeutic Targets 2016Angelman syndrome (AS) is a neurodevelopmental disorder caused by deficiency of maternally inherited UBE3A, an ubiquitin E3 ligase. Despite recent progress in... (Review)
Review
INTRODUCTION
Angelman syndrome (AS) is a neurodevelopmental disorder caused by deficiency of maternally inherited UBE3A, an ubiquitin E3 ligase. Despite recent progress in understanding the mechanism underlying UBE3A imprinting, there is no effective treatment. Further investigation of the roles played by UBE3A in the central nervous system (CNS) is needed for developing effective therapies.
AREA COVERED
This review covers the literature related to genetic classifications of AS, recent discoveries regarding the regulation of UBE3A imprinting, alterations in cell signaling in various brain regions and potential therapeutic approaches. Since a large proportion of AS patients exhibit comorbid autism spectrum disorder (ASD), potential common molecular bases are discussed.
EXPERT OPINION
Advances in understanding UBE3A imprinting provide a unique opportunity to induce paternal UBE3A expression, thus targeting the syndrome at its 'root.' However, such efforts have yielded less-than-expected rescue effects in AS mouse models, raising the concern that activation of paternal UBE3A after a critical period cannot correct all the CNS defects that developed in a UBE3A-deficient environment. On the other hand, targeting abnormal downstream cell signaling pathways has provided promising rescue effects in preclinical research. Thus, combined reinstatement of paternal UBE3A expression with targeting abnormal signaling pathways should provide better therapeutic effects.
Topics: Angelman Syndrome; Animals; Humans; Ubiquitin-Protein Ligases
PubMed: 26558806
DOI: 10.1517/14728222.2016.1115837 -
Journal of Medical Genetics Feb 2003Angelman syndrome (AS) is a neurodevelopmental disorder characterised by severe learning difficulties, ataxia, a seizure disorder with a characteristic EEG, subtle... (Review)
Review
Angelman syndrome (AS) is a neurodevelopmental disorder characterised by severe learning difficulties, ataxia, a seizure disorder with a characteristic EEG, subtle dysmorphic facial features, and a happy, sociable disposition. Most children present with delay in developmental milestones and slowing of head growth during the first year of life. In the majority of cases speech does not develop. Patients with AS have a characteristic behavioural phenotype with jerky movements, frequent and sometimes inappropriate laughter, a love of water, and sleep disorder. The facial features are subtle and include a wide, smiling mouth, prominent chin, and deep set eyes. It is caused by a variety of genetic abnormalities involving the chromosome 15q11-13 region, which is subject to genomic imprinting. These include maternal deletion, paternal uniparental disomy, imprinting defects, and point mutations or small deletions within the UBE3A gene, which lies within this region. UBE3A shows tissue specific imprinting, being expressed exclusively from the maternal allele in brain. The genetic mechanisms identified so far in AS are found in 85-90% of those with the clinical phenotype and all interfere with UBE3A expression.
Topics: Angelman Syndrome; Chromosome Deletion; Chromosomes, Human, Pair 15; Genetic Counseling; Genomic Imprinting; Genotype; Humans; Ligases; Mutation; Phenotype; Ubiquitin-Protein Ligases; Uniparental Disomy
PubMed: 12566516
DOI: 10.1136/jmg.40.2.87 -
Brain and Language Jan 2023Angelman syndrome (AS) is known to affect expressive and receptive communication abilities. This study examined individual differences in neural mechanisms underlying...
Angelman syndrome (AS) is known to affect expressive and receptive communication abilities. This study examined individual differences in neural mechanisms underlying speech processing in children with AS (n = 24, M age = 10.01 years) and typical development (n = 30, M age = 10.82 years) using auditory event-related potentials during passive listening to common English words and novel pseudowords. A group of adults with AS (n = 7, M = 31.78 years) provided data about the upper developmental range. The typically developing group demonstrated the expected more negative amplitudes in response to words than pseudowords within 250-500 ms after stimulus onset at the left temporal scalp region. Children and adults with AS exhibited a similar left-lateralized pattern of word-pseudoword differentiation at temporal and parietal regions, but not the midline parietal memory response for known words observed in the typically developing group, suggesting typical-like word-pseudoword differentiation along with possible alterations in the automatic recall of word meaning. These results have important implications for understanding receptive and expressive communication processes in AS and support the use of auditory neural responses for characterizing individual differences in neurodevelopmental disorders with limited speech.
Topics: Adult; Child; Humans; Angelman Syndrome; Word Processing; Evoked Potentials; Language; Communication; Speech Perception
PubMed: 36502770
DOI: 10.1016/j.bandl.2022.105215 -
Molecular Autism Feb 2021Angelman Syndrome (AS) is a rare genetic disorder characterized by impaired communication, motor and balance deficits, intellectual disabilities, recurring seizures and...
BACKGROUND
Angelman Syndrome (AS) is a rare genetic disorder characterized by impaired communication, motor and balance deficits, intellectual disabilities, recurring seizures and abnormal sleep patterns. The genetic cause of AS is neuronal-specific loss of expression of UBE3A (ubiquitin-protein ligase E6-AP), an imprinted gene. Seizure and sleep disorders are highly prevalent (> 80%) in the AS population. The present experiments were designed to identify translational, neurophysiological outcome measures in a model of AS.
METHODS
We used the exon-2 deletion mouse (Ube3a-del) on a C57BL/6J background to assess seizure, sleep and electrophysiological phenotypes. Seizure susceptibility has been reported in Ube3a-del mice with a variety of seizure induction methods. Here, we provoked seizures by a single high-dose injection of 80 mg/kg pentylenetetrazole. Novel experiments included the utilization of wireless telemetry devices to acquire global electroencephalogram (EEG) and neurophysiological data on electrographic seizures, power spectra, light-dark cycles, sleep stages and sleep spindles in Ube3a-del and WT mice.
RESULTS
Ube3a-del mice exhibited reduced seizure threshold compared to WT. EEG illustrated that Ube3a-del mice had increased epileptiform spiking activity and delta power, which corroborates findings from other laboratories and recapitulates clinical reports in AS. This is the first report to use a cortical surface-based recording by a wireless telemetry device over tethered/fixed head-mount depth recordings. Less time in both paradoxical and slow-wave sleep, longer latencies to paradoxical sleep stages and total less sleep time in Ube3a-del mice were observed compared to WT. For the first time, we detected fewer sleep spindles in the AS mouse model.
LIMITATIONS
This study was limited to the exon 2 deletion mouse model, and future work will investigate the rat model of AS, containing a complete Ube3a deletion and pair EEG with behavior.
CONCLUSIONS
Our data enhance rigor and translatability as our study provides important corroboration of previous reports on epileptiform and elevated delta power. For the first time we report neurophysiological phenotypes collected via translational methodology. Furthermore, this is the first report of reduced sleep spindles, a critical marker of memory consolidation during sleep, in an AS model. Our results are useful outcomes for therapeutic testing.
Topics: Angelman Syndrome; Animals; Disease Models, Animal; Electroencephalography; Genetic Association Studies; Genetic Predisposition to Disease; Mice; Mice, Knockout; Phenotype; Photoperiod; Sleep Wake Disorders; Ubiquitin-Protein Ligases
PubMed: 33549123
DOI: 10.1186/s13229-021-00416-y -
Journal of Intellectual Disability... Nov 2022Angelman syndrome (AS) is a neurogenetic disorder that causes severe intellectual disability, expressive language deficits, motor impairment, ataxia, sleep problems,...
BACKGROUND
Angelman syndrome (AS) is a neurogenetic disorder that causes severe intellectual disability, expressive language deficits, motor impairment, ataxia, sleep problems, epileptic seizures and a happy disposition. People with AS frequently experience gastrointestinal (GI) symptoms.
METHOD
This study used data from the Global Angelman Syndrome Registry to explore the relationship between early and current GI symptoms and co-morbidity in children and adolescents with AS (n = 173). Two groups that experienced a high (n = 91) and a low (n = 82) frequency of GI symptoms were examined in relation to feeding and GI history in infancy, sleep and toileting problems, levels of language and communication and challenging behaviours. Predictors of GI symptoms were then investigated using a series of logistic regressions.
RESULTS
This analysis found that constipation and gastroesophageal reflux affected 84% and 64%, of the sample, respectively. The high frequency of GI symptoms were significantly associated with: 'refusal to nurse', 'vomiting', 'arching', 'difficulty gaining weight', gastroesophageal reflux, 'solid food transition', frequency of night-time urinary continence and sleep hyperhidrosis during infancy. GI symptoms were not significantly associated with sleep, toileting, language or challenging behaviours. Significant predictors of high frequency GI symptoms were gastroesophageal reflux and sleep hyperhidrosis.
CONCLUSIONS
Future research needs to investigate the association between AS and GI co-morbidity in adults with AS.
Topics: Adolescent; Adult; Angelman Syndrome; Child; Gastroesophageal Reflux; Gastrointestinal Diseases; Humans; Hyperhidrosis; Morbidity
PubMed: 36052644
DOI: 10.1111/jir.12975 -
Molecular Autism 2018Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, speech and motor impairments, epilepsy, abnormal sleep, and phenotypic...
BACKGROUND
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, speech and motor impairments, epilepsy, abnormal sleep, and phenotypic overlap with autism. Individuals with AS display characteristic EEG patterns including high-amplitude rhythmic delta waves. Here, we sought to quantitatively explore EEG architecture in AS beyond known spectral power phenotypes. We were motivated by studies of functional connectivity and sleep spindles in autism to study these EEG readouts in children with AS.
METHODS
We analyzed retrospective wake and sleep EEGs from children with AS (age 4-11) and age-matched neurotypical controls. We assessed long-range and short-range functional connectivity by measuring coherence across multiple frequencies during wake and sleep. We quantified sleep spindles using automated and manual approaches.
RESULTS
During wakefulness, children with AS showed enhanced long-range EEG coherence across a wide range of frequencies. During sleep, children with AS showed increased long-range EEG coherence specifically in the gamma band. EEGs from children with AS contained fewer sleep spindles, and these spindles were shorter in duration than their neurotypical counterparts.
CONCLUSIONS
We demonstrate two quantitative readouts of dysregulated sleep composition in children with AS-gamma coherence and spindles-and describe how functional connectivity patterns may be disrupted during wakefulness. Quantitative EEG phenotypes have potential as biomarkers and readouts of target engagement for future clinical trials and provide clues into how neural circuits are dysregulated in children with AS.
Topics: Angelman Syndrome; Case-Control Studies; Child; Delta Rhythm; Female; Gamma Rhythm; Humans; Male; Sleep Stages
PubMed: 29719672
DOI: 10.1186/s13229-018-0214-8 -
Science (New York, N.Y.) Dec 2019Disruptions in the ubiquitin protein ligase E3A () gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity...
Disruptions in the ubiquitin protein ligase E3A () gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases.
Topics: Angelman Syndrome; Animals; Calcium Channels, N-Type; Epilepsy; Humans; Mice; Models, Neurological; Neurons; Organoids; Potassium Channel Blockers; Seizures; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 31857479
DOI: 10.1126/science.aav5386 -
Human Genetics Dec 2022Angelman syndrome is a rare neurodevelopmental disorder caused by mutations affecting the chromosomal 15q11-13 region, either by contiguous gene deletions, imprinting... (Review)
Review
Angelman syndrome is a rare neurodevelopmental disorder caused by mutations affecting the chromosomal 15q11-13 region, either by contiguous gene deletions, imprinting defects, uniparental disomy, or mutations in the UBE3A gene itself. Phenotypic abnormalities are driven primarily, but not exclusively (especially in 15q11-13 deletion cases) by loss of expression of the maternally inherited UBE3A gene expression. The disorder was first described in 1965 by the English pediatrician Harry Angelman. Since that first description of three children with Angelman syndrome, there has been extensive research into the genetic, molecular and phenotypic aspects of the disorder. In the last decade, this has resulted in over 100 publications per year. Collectively, this research has led the field to a pivotal point in which restoring UBE3A function by genetic therapies is currently explored in several clinical trials. In this study, we employed a bibliometric approach to review and visualize the development of Angelman syndrome research over the last 50 years. We look into different parameters shaping the progress of the Angelman syndrome research field, including source of funding, publishing journals and international collaborations between research groups. Using a network approach, we map the focus of the research field and how that shifted over time. This overview helps understand the shift of research focus in the field and can provide a comprehensive handbook of Angelman syndrome research development.
Topics: Child; Humans; Angelman Syndrome; Ubiquitin-Protein Ligases; Mutation; Bibliometrics; Chromosomes, Human, Pair 15
PubMed: 35637341
DOI: 10.1007/s00439-022-02460-x