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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 -
Zhonghua Er Ke Za Zhi = Chinese Journal... Jul 2023
Topics: Humans; Angelman Syndrome
PubMed: 37385816
DOI: 10.3760/cma.j.cn112140-20230322-00198 -
Epilepsy Research Feb 2024Angelman syndrome (AS) is a rare neurodevelopmental disorder that is typically caused by deletion or a loss-of-function mutation of the maternal copy of the ubiquitin... (Review)
Review
Angelman syndrome (AS) is a rare neurodevelopmental disorder that is typically caused by deletion or a loss-of-function mutation of the maternal copy of the ubiquitin ligase E3A (UBE3A) gene. The disorder is characterized by severe intellectual disability, deficits in speech, motor abnormalities, altered electroencephalography (EEG) activity, spontaneous epileptic seizures, sleep disturbances, and a happy demeanor with frequent laughter. Regarding electrophysiologic abnormalities in particular, enhanced delta oscillatory power and an elevated excitatory/inhibitory (E/I) ratio have been documented in AS, with E/I ratio especially studied in rodent models. These electrophysiologic characteristics appear to relate with the greatly elevated rates of epilepsy in individuals with AS, and associated hypersynchronous neural activity. Here we briefly review findings on EEG, E/I ratio, and epileptic seizures in AS, including data from rodent models of the disorder. We summarize pharmacologic approaches that have been used to treat behavioral aspects of AS, including neuropsychiatric phenomena and sleep disturbances, as well as seizures in the context of the disorder. Antidepressants such as SSRIs and atypical antipsychotics are among the medications that have been used behaviorally, whereas anticonvulsant drugs such as valproic acid and lamotrigine have frequently been used to control seizures in AS. We end by suggesting novel uses for some existing pharmacologic agents in AS, including noradrenergic transmission reducing drugs (alpha2 agonists, beta blockers, alpha1 antagonists) and cholinesterase inhibitors, where these various classes of drugs may have the ability to ameliorate both behavioral disturbances and seizures.
Topics: Humans; Angelman Syndrome; Seizures; Epilepsy; Electroencephalography; Valproic Acid; Anticonvulsants
PubMed: 38217951
DOI: 10.1016/j.eplepsyres.2024.107286 -
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 -
European Journal of Paediatric... Nov 2023To evaluate efficacy and safety of gaboxadol for treatment of children with Angelman syndrome (AS). (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To evaluate efficacy and safety of gaboxadol for treatment of children with Angelman syndrome (AS).
METHOD
In this international, double-blind, phase 3 trial, we randomized children 4-12 years old with a molecular diagnosis of AS and a Clinical Global Impression (CGI)-severity score ≥3 to either daily administration of weight-based gaboxadol or matching placebo for 12 weeks. The primary endpoint was the CGI-Improvement-AS (CGI-I-AS) score at week 12. Secondary endpoints included the proportion of participants with CGI-I-AS response of ≤3 (i.e., at least "minimal improvement") and ≤2 (i.e., at least "much improvement") at week 12. Safety and tolerability were monitored throughout the study. Weight based dosing of study drug ranged from 0.125 mg/kg to 0.24 mg/kg depending on weight range.
RESULTS
Between August 2019 and November 2020, 104 participants were enrolled: participants 4-12 years old were randomly (1:1) assigned to gaboxadol (n = 47) or placebo (n = 50), and 7 other participants 2─3 years old who received gaboxadol and were assessed for safety only. All gaboxadol-treated participants and 48 of 50 placebo-treated participants completed treatment. There was no significant difference in CGI-I-AS between groups: at week 12, mean CGI-I-AS score was 3.3 (SD, 1.00) and 3.2 (SD, 1.05) in the gaboxadol and placebo groups, respectively, yielding a least squares mean difference of zero (p = 0.83). There were no between-group significant differences with respect to CGI-I-AS responses. Gaboxadol was well tolerated in all age groups of this study.
CONCLUSIONS
There was no significant difference in CGI-I-AS between gaboxadol and placebo after 12 weeks of study treatment in pediatric AS participants.
CLINICALTRIALS
GOV: NCT04106557.
Topics: Child; Child, Preschool; Humans; Angelman Syndrome; Double-Blind Method; Isoxazoles; Treatment Outcome
PubMed: 37639777
DOI: 10.1016/j.ejpn.2023.07.008 -
Frontiers in Molecular Neuroscience 2019UBE3A is a gene implicated in neurodevelopmental disorders. The protein product of UBE3A is the E3 ligase E6-associated protein (E6AP), and its expression in the brain... (Review)
Review
UBE3A is a gene implicated in neurodevelopmental disorders. The protein product of UBE3A is the E3 ligase E6-associated protein (E6AP), and its expression in the brain is uniquely regulated genetic imprinting. Loss of E6AP expression leads to the development of Angelman syndrome (AS), clinically characterized by lack of speech, abnormal motor development, and the presence of seizures. Conversely, copy number variations (CNVs) that result in the overexpression of E6AP are strongly associated with the development of autism spectrum disorders (ASDs), defined by decreased communication, impaired social interest, and increased repetitive behavior. In this review article, we focus on the neurobiological function of Ube3A/E6AP. As an E3 ligase, many functional target proteins of E6AP have been discovered, including p53, Arc, Ephexin5, and SK2. On a neuronal level, E6AP is widely expressed within the cell, including dendritic arbors, spines, and the nucleus. E6AP regulates neuronal morphological maturation and plays an important role in synaptic plasticity and cortical development. These molecular findings provide insight into our understanding of the molecular events underlying AS and ASDs.
PubMed: 31114479
DOI: 10.3389/fnmol.2019.00109 -
Sleep Medicine Reviews Feb 2018Sleep problems are reported to be extremely prevalent in individuals with developmental disabilities. The consensus guidelines for Angelman syndrome (AS) consider... (Meta-Analysis)
Meta-Analysis Review
Sleep problems are reported to be extremely prevalent in individuals with developmental disabilities. The consensus guidelines for Angelman syndrome (AS) consider abnormal sleep-wake cycles and diminished need for sleep as associated features. We report an integrative research review and a meta-analysis of studies with sleep as the primary aim of investigation in an AS sample. 14 studies met eligibility criteria with half of them being surveys. Thirteen of the 17 conceptually formed sleep disorder item-groups showed to be significant for individuals with AS. There is evidence that arousal during sleep, somnolence and possibly short sleep duration are the primary sleep problems in individuals with AS. According to the results of this review and meta-analyses, there is clear evidence for sleep problems in individuals with AS. Individual effect sizes remain overall small, but nevertheless findings suggest disorders of arousal and sleepiness to be distinctive. In light of these findings, other sleep complaints in individuals with AS should be carefully examined. Consistent standards for research on sleep in individuals with AS are critical for new lines of investigation.
Topics: Actigraphy; Angelman Syndrome; Arousal; Humans; Polysomnography; Sleep; Sleep Wake Disorders
PubMed: 28784434
DOI: 10.1016/j.smrv.2017.01.002 -
Journal of Autism and Developmental... Aug 2022Anxiety is being increasingly identified in Angelman syndrome (AS). Qualitative questions and quantitative assessments were used to evaluate for anxiety in 50 subjects...
Anxiety is being increasingly identified in Angelman syndrome (AS). Qualitative questions and quantitative assessments were used to evaluate for anxiety in 50 subjects with AS. In-person evaluations assessed behaviors concerning for anxiety and circumstances wherein they occurred. Caregivers completed anxiety and other behavioral rating scales. Caregiver responses were categorized and compared to items from anxiety rating scales. The most common behavioral manifestation of anxiety was "aggression." The most common circumstance was "separation from caregiver/parent." Subjects had elevated scores on anxiety, irritability and hyperactivity scales with lower mean scores among subjects with a maternal deletion. The Pediatric Anxiety Rating Scale best captured behaviors described by caregivers. Existing anxiety scales should be adapted for use in AS.
Topics: Angelman Syndrome; Anxiety; Autism Spectrum Disorder; Caregivers; Child; Humans; Parents; Psychiatric Status Rating Scales
PubMed: 34417655
DOI: 10.1007/s10803-021-05238-8 -
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 -
Ci Ji Yi Xue Za Zhi = Tzu-chi Medical... 2020Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are considered sister imprinting disorders. Although both AS and PWS congenital neurodevelopmental disorders have... (Review)
Review
Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are considered sister imprinting disorders. Although both AS and PWS congenital neurodevelopmental disorders have chromosome 15q11.3-q13 dysfunction, their molecular mechanisms differ owing to genomic imprinting, which results in different parent-of-the-origin gene expressions. Recently, several randomized controlled trials have been proceeded to treat specific symptoms of AS and PWS. Due to the advance of clinical management, early diagnosis for patients with AS and PWS is important. PWS is induced by multiple paternal gene dysfunctions, including those in MKRN3, MAGEL2, NDN, SNURF-SNPRPN, NPAP1, and a cluster of small nucleolar RNA genes. PWS patients exhibit characteristic facial features, endocrinological, and behavioral phenotypes, including short and obese figures, hyperphagia, growth hormone deficiency, hypogonadism, autism, or obsessive- compulsive-like behaviors. In addition, hypotonia, poor feeding, failure to thrive, and typical facial features are major factors for early diagnosis of PWS. For PWS patients, epilepsy is not common and easy to treat. Conversely, AS is a single-gene disorder induced by ubiquitin-protein ligase E3A dysfunction, which only expresses from a maternal allele. AS patients develop epilepsy in their early lives and their seizures are difficult to control. The distinctive gait pattern, excessive laughter, and characteristic electroencephalography features, which contain anterior-dominated, high-voltage triphasic delta waves intermixed with epileptic spikes, result in early suspicion of AS. Often, polytherapy, including the combination of valproate, levetiracetam, lamotrigine, and benzodiazepines, is required for controlling seizures of AS patients. Notably, carbamazepine, oxcarbazepine, and vigabatrin should be avoided, since these may induce nonconvulsive status epilepticus. AS and PWS presented with distinct clinical manifestations according to specific molecular defects due to genomic imprinting. Early diagnosis and teamwork intervention, including geneticists, neurologists, rehabilitation physicians, and pulmonologists, are important. Epilepsy is common in patients with AS, and after proper treatment, seizures could be effectively controlled in late childhood or early adulthood for both AS and PWS patients.
PubMed: 32269945
DOI: 10.4103/tcmj.tcmj_103_19