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The FEBS Journal Jun 2020Angelman syndrome (AS) is an incurable neurodevelopmental disease caused by loss of function of the maternally inherited UBE3A gene. AS is characterized by a defined set... (Review)
Review
Angelman syndrome (AS) is an incurable neurodevelopmental disease caused by loss of function of the maternally inherited UBE3A gene. AS is characterized by a defined set of symptoms, namely severe developmental delay, speech impairment, uncontrolled laughter, and ataxia. Current understanding of the pathophysiology of AS relies mostly on studies using the murine model of the disease, although alternative models based on patient-derived stem cells are now emerging. Here, we summarize the literature of the last decade concerning the three major brain areas that have been the subject of study in the context of AS: hippocampus, cortex, and the cerebellum. Our comprehensive analysis highlights the major phenotypes ascribed to the different brain areas. Moreover, we also discuss the major drawbacks of current models and point out future directions for research in the context of AS, which will hopefully lead us to an effective treatment of this condition in humans.
Topics: Angelman Syndrome; Animals; Brain; Cerebellar Cortex; Cerebellum; Hippocampus; Humans; Loss of Function Mutation; Mice; Neurodevelopmental Disorders; Ubiquitin-Protein Ligases
PubMed: 32087041
DOI: 10.1111/febs.15258 -
Neurotherapeutics : the Journal of the... Jul 2015In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is... (Review)
Review
In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1-2% of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.
Topics: Angelman Syndrome; Animals; Autism Spectrum Disorder; Brain; Clinical Trials as Topic; Disease Models, Animal; Female; Humans; Male; Mice; Mutation; Neurons; Ubiquitin-Protein Ligases
PubMed: 26040994
DOI: 10.1007/s13311-015-0361-y -
Genes Jun 2021Angelman syndrome (AS) is a rare neurodevelopmental disease that is caused by the loss of function of the maternal copy of ubiquitin-protein ligase E3A () on the... (Review)
Review
Angelman syndrome (AS) is a rare neurodevelopmental disease that is caused by the loss of function of the maternal copy of ubiquitin-protein ligase E3A () on the chromosome 15q11-13 region. AS is characterized by global developmental delay, severe intellectual disability, lack of speech, happy disposition, ataxia, epilepsy, and distinct behavioral profile. There are four molecular mechanisms of etiology: maternal deletion of chromosome 15q11-q13, paternal uniparental disomy of chromosome 15q11-q13, imprinting defects, and maternally inherited UBE3A mutations. Different genetic types may show different phenotypes in performance, seizure, behavior, sleep, and other aspects. AS caused by maternal deletion of 15q11-13 appears to have worse development, cognitive skills, albinism, ataxia, and more autistic features than those of other genotypes. Children with a mutation have less severe phenotypes and a nearly normal development quotient. In this review, we proposed to review genotype-phenotype correlations based on different genotypes. Understanding the pathophysiology of the different genotypes and the genotype-phenotype correlations will offer an opportunity for individualized treatment and genetic counseling. Genotype-phenotype correlations based on larger data should be carried out for identifying new treatment modalities.
Topics: Angelman Syndrome; Chromosomes, Human, Pair 15; Genetic Association Studies; Genetic Counseling; Genotype; Humans; Mutation; Phenotype; Seizures; Ubiquitin-Protein Ligases
PubMed: 34203304
DOI: 10.3390/genes12070987 -
Pediatric Clinics of North America Jun 2015Three distinct neurodevelopmental disorders arise primarily from deletions or duplications that occur at the 15q11-q13 locus: Prader-Willi syndrome, Angelman syndrome,... (Review)
Review
Three distinct neurodevelopmental disorders arise primarily from deletions or duplications that occur at the 15q11-q13 locus: Prader-Willi syndrome, Angelman syndrome, and 15q11-q13 duplication syndrome. Each of these disorders results from the loss of function or overexpression of at least 1 imprinted gene. This article discusses the clinical background, genetic cause, diagnostic strategy, and management of each of these 3 disorders.
Topics: Angelman Syndrome; Child; Chromosome Aberrations; Chromosomes, Human, Pair 15; DNA Methylation; Epigenesis, Genetic; Gene Dosage; Gene Duplication; Gene Expression; Humans; Intellectual Disability; Prader-Willi Syndrome
PubMed: 26022164
DOI: 10.1016/j.pcl.2015.03.004 -
Expert Review of Neurotherapeutics 2023Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, limited expressive language, epilepsy, and motor impairment. Angelman... (Review)
Review
INTRODUCTION
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, limited expressive language, epilepsy, and motor impairment. Angelman syndrome is caused by haploinsufficiency of the UBE3A gene on the maternal copy of chromosome 15. There have been ongoing advances in the understanding of neurological, behavioral, and sleep-based problems and associated treatments for patients with AS. These results along with gene-based therapies entering into clinical development prompted this review.
AREAS COVERED
The authors summarize the research basis describing phenomenology of epilepsy and behavioral concerns such as hyperactivity behavior, aggression, self-injury, repetitive behavior, and sleep disorder. The evidence for recent treatment advances in these target symptom domains of concern is reviewed, and the potential for emerging gene therapy treatments is considered.
EXPERT OPINION
The prospect for emerging gene therapies means that increasing efforts should be directed toward the early identification of AS implemented equitably. Recent studies emphasize the important role of behavioral therapy in addressing mental health concerns such as aggression and disordered sleep.
Topics: Humans; Angelman Syndrome; Cognition; Aggression; Behavior Therapy; Epilepsy
PubMed: 37599585
DOI: 10.1080/14737175.2023.2245568 -
Molecular Genetics & Genomic Medicine Mar 2022Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment,... (Review)
Review
BACKGROUND
Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence-based literature. We present a consensus statement and comprehensive literature review that proposes a standard of care practices for the management of AS at a critical time when therapeutics to alter the natural history of the disease are on the horizon.
METHODS
We compiled the key recognized clinical features of AS based on consensus from a team of specialists managing patients with AS. Working groups were established to address each focus area with committees comprised of providers who manage >5 individuals. Committees developed management guidelines for their area of expertise. These were compiled into a final document to provide a framework for standardizing management. Evidence from the medical literature was also comprehensively reviewed.
RESULTS
Areas covered by working groups in the consensus document include genetics, developmental medicine, psychology, general health concerns, neurology (including movement disorders), sleep, psychiatry, orthopedics, ophthalmology, communication, early intervention and therapies, and caregiver health. Working groups created frameworks, including flowcharts and tables, to help with quick access for providers. Data from the literature were incorporated to ensure providers had review of experiential versus evidence-based care guidelines.
CONCLUSION
Standards of care in the management of AS are keys to ensure optimal care at a critical time when new disease-modifying therapies are emerging. This document is a framework for providers of all familiarity levels.
Topics: Angelman Syndrome; Humans; Standard of Care
PubMed: 35150089
DOI: 10.1002/mgg3.1843 -
Brain & Development Jan 2021Angelman Syndrome (AS) is characterized by severe developmental delays including marked speech impairment, movement abnormalities(ataxia, tremor), and unique behaviors... (Review)
Review
Angelman Syndrome (AS) is characterized by severe developmental delays including marked speech impairment, movement abnormalities(ataxia, tremor), and unique behaviors such as frequent laughter and is caused by dysfunctional maternal UBE3A gene (maternal 15q11-13 deletions, maternal specific UBE3A mutation, uniparental disomy, and imprinting defect). Intractable epileptic seizures since early childhood with characteristic EEG abnormalities are present in 80-90% patients with AS. Underlying pathophysiology may involve neocortical and thalamocortical hyperexcitability secondary to severe reduction of GABAergic input, as well as dysfunctional synaptic plasticity, deficient synaptogenesis, and neuronal morphological immaturity. The onset of epilepsy is most prevalent between 1 and 3 years of age; however, approximately 25% of patients developed epilepsy before one year of age. Various types of generalized seizures are most prevalent, with most common types are myoclonic and atypical absence.More than 95% of epilepsy patients may have daily seizures at least for a limited time during early childhood, and two-third patients develop disabling seizures. Fever provoked seizures, and frequent occurrence of nonconvulsive status epilepticus are two unique features. Seizures are frequently pharmacoresistant. Considering underlying prominent GABAergic dysfunction, clinicians had used AEDs that target GABAergic signaling such as valproate, phenobarbital, and clonazepam as first-line therapies for AS. However, due to the unfavorable side effect profile of these AEDs, a recent treatment approach involves priority use of levetiracetam, clobazam, topiramate, lamotrigine, ethosuximide, VNS, and carbohydrate-restricted diets. Besides symptomatic management, there has been recent progress to find a curative treatment with the following approaches: 1. Gene/protein replacement therapy (Adeno and lentiviral vector therapy to deliver a gene or secretory protein); 2. Activation of the intact but silent paternal copy of UBE3A (antisense oligonucleotide therapy and artificial transcription factors); and 3. Downstream therapies (OV101/gaboxadol, ketone supplement, novel compounds/peptides, anti-inflammatory/regenerative therapy).
Topics: Angelman Syndrome; Anticonvulsants; Child; Child, Preschool; Electroencephalography; Epilepsy; Female; Humans; Infant; Infant, Newborn; Male; Seizures; Status Epilepticus; Ubiquitin-Protein Ligases; Valproic Acid
PubMed: 32893075
DOI: 10.1016/j.braindev.2020.08.014 -
Nature Reviews. Neurology Oct 2016Angelman syndrome is a rare neurogenetic disorder that is characterized by microcephaly, severe intellectual deficit, speech impairment, epilepsy, EEG abnormalities,... (Review)
Review
Angelman syndrome is a rare neurogenetic disorder that is characterized by microcephaly, severe intellectual deficit, speech impairment, epilepsy, EEG abnormalities, ataxic movements, tongue protrusion, paroxysms of laughter, abnormal sleep patterns, and hyperactivity. Angelman syndrome results from loss of function of the imprinted UBE3A (ubiquitin-protein ligase E3A) gene on chromosome 15q11.2-q13. This loss of function can be caused by a mutation on the maternal allele, a 5-7 Mb deletion of the maternally inherited chromosomal region, paternal uniparental disomy of chromosome 15, or an imprinting defect. The chromosomal deletion tends to cause the most severe symptoms, possibly owing to co-deletion of GABA receptor genes. UBE3A mutations and imprinting defects can be associated with a high risk of recurrence within families. Disruption of UBE3A function in neurons seems to inhibit synapse formation and experience-dependent synapse remodelling. Clinical diagnosis of Angelman syndrome in infants and young children is sometimes difficult, but can be verified by genetic tests. At present, treatment of symptoms such as seizures is the only medical strategy, but genetic therapies aimed at activating the silent copy of UBE3A on the paternal allele are conceivable.
Topics: Angelman Syndrome; Animals; Humans; Ubiquitin-Protein Ligases
PubMed: 27615419
DOI: 10.1038/nrneurol.2016.133 -
Science (New York, N.Y.) Sep 2023Inactivation of the ubiquitin ligase Ube3a causes the developmental disorder Angelman syndrome, whereas increased Ube3a dosage is associated with autism spectrum...
Inactivation of the ubiquitin ligase Ube3a causes the developmental disorder Angelman syndrome, whereas increased Ube3a dosage is associated with autism spectrum disorders. Despite the enriched localization of Ube3a in the axon terminals including presynapses, little is known about the presynaptic function of Ube3a and mechanisms underlying its presynaptic localization. We show that developmental synapse elimination requires presynaptic Ube3a activity in neurons. We further identified the domain of Ube3a that is required for its interaction with the kinesin motor. Angelman syndrome-associated missense mutations in the interaction domain attenuate presynaptic targeting of Ube3a and prevent synapse elimination. Conversely, increased Ube3a activity in presynapses leads to precocious synapse elimination and impairs synaptic transmission. Our findings reveal the physiological role of Ube3a and suggest potential pathogenic mechanisms associated with Ube3a dysregulation.
Topics: Animals; Angelman Syndrome; Autism Spectrum Disorder; Down-Regulation; Drosophila Proteins; Synaptic Transmission; Ubiquitin-Protein Ligases; Drosophila melanogaster; Synapses
PubMed: 37708280
DOI: 10.1126/science.ade8978 -
Science Translational Medicine Mar 2023Angelman syndrome is a devastating neurogenetic disorder for which there is currently no effective treatment. It is caused by mutations or epimutations affecting the...
Angelman syndrome is a devastating neurogenetic disorder for which there is currently no effective treatment. It is caused by mutations or epimutations affecting the expression or function of the maternally inherited allele of the ubiquitin-protein ligase E3A () gene. The paternal allele is imprinted in neurons of the central nervous system (CNS) by the antisense () transcript, which represents the distal end of the small nucleolar host gene 14 () transcription unit. Reactivating the expression of the paternal allele in the CNS has long been pursued as a therapeutic option for Angelman syndrome. Here, we described the development of an antisense oligonucleotide (ASO) therapy for Angelman syndrome that targets an evolutionarily conserved region demarcating the start of the transcript. We designed and chemically optimized gapmer ASOs targeting specific sequences at the start of the human transcript. We showed that ASOs targeting this region precisely and efficiently repress the transcription of , reactivating the expression of the paternal allele in neurotypical and Angelman syndrome induced pluripotent stem cell-derived neurons. We further showed that human-targeted ASOs administered to the CNS of cynomolgus macaques by lumbar intrathecal injection repress and reactivate the expression of the paternal allele throughout the CNS. These findings support the advancement of this investigational molecular therapy for Angelman syndrome into clinical development (ClinicalTrials.gov, NCT04259281).
Topics: Humans; Angelman Syndrome; Alleles; Ubiquitin-Protein Ligases
PubMed: 36947593
DOI: 10.1126/scitranslmed.abf4077