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Trends in Neurosciences Jun 2011Angelman syndrome (AS) is a severe genetic disorder caused by mutations or deletions of the maternally inherited UBE3A gene. UBE3A encodes an E3 ubiquitin ligase that is... (Review)
Review
Angelman syndrome (AS) is a severe genetic disorder caused by mutations or deletions of the maternally inherited UBE3A gene. UBE3A encodes an E3 ubiquitin ligase that is expressed biallelically in most tissues but is maternally expressed in almost all neurons. In this review, we describe recent advances in understanding the expression and function of UBE3A in the brain and the etiology of AS. We highlight current AS model systems, epigenetic mechanisms of UBE3A regulation, and the identification of potential UBE3A substrates in the brain. In the process, we identify major gaps in our knowledge that, if bridged, could move us closer to identifying treatments for this debilitating neurodevelopmental disorder.
Topics: Angelman Syndrome; Animals; Brain; Gene Expression; Gene Expression Regulation; Genomic Imprinting; Humans; Mice; Phenotype; Ubiquitin-Protein Ligases
PubMed: 21592595
DOI: 10.1016/j.tins.2011.04.001 -
BMC Neuroscience Jun 2014Angelman syndrome is a monogenic neurologic disorder that affects 1 in 15,000 children, and is characterized by ataxia, intellectual disability, speech impairment, sleep... (Review)
Review
BACKGROUND
Angelman syndrome is a monogenic neurologic disorder that affects 1 in 15,000 children, and is characterized by ataxia, intellectual disability, speech impairment, sleep disorders, and seizures. The disorder is caused by loss of central nervous system expression of UBE3A, a gene encoding a ubiquitin ligase. Current treatments focus on the management of symptoms, as there have not been therapies to treat the underlying molecular cause of the disease. However, this outlook is evolving with advances in molecular therapies, including artificial transcription factors a class of engineered DNA-binding proteins that have the potential to target a specific site in the genome.
RESULTS
Here we review the recent progress and prospect of targeted gene expression therapies. Three main issues that must be addressed to advance toward human clinical trials are specificity, toxicity, and delivery.
CONCLUSIONS
Artificial transcription factors have the potential to address these concerns on a level that meets and in some cases exceeds current small molecule therapies. We examine the possibilities of such approaches in the context of Angelman syndrome, as a template for other single-gene, neurologic disorders.
Topics: Angelman Syndrome; Brain; Humans; Molecular Targeted Therapy; Neuroprotective Agents; Ubiquitin-Protein Ligases
PubMed: 24946931
DOI: 10.1186/1471-2202-15-76 -
Developmental Medicine and Child... Nov 2019A scoping review was conducted to examine and evaluate empirical data on the communication profile of Angelman syndrome beyond the described dissociation between... (Review)
Review
AIM
A scoping review was conducted to examine and evaluate empirical data on the communication profile of Angelman syndrome beyond the described dissociation between receptive language and speech.
METHOD
Three databases (PsycINFO, Embase, and Web of Science) were searched to retrieve articles investigating communication in Angelman syndrome. Seventeen articles investigating the broader communication profile were found; their methodology was evaluated against quality criteria.
RESULTS
Despite the absence of speech, individuals with Angelman syndrome have a wide repertoire of non-verbal communicative behaviours, mainly characterized by gestures, although advanced forms such as symbolic communication are used by some individuals. The use of communicative forms differs between the genetic aetiologies of Angelman syndrome; individuals with non-deletion aetiologies typically have greater communicative abilities.
INTERPRETATION
The broader communication profile of Angelman syndrome is characterized by diverse and multimodal abilities, including some use of symbolic forms of communication that appears atypical given the absence of speech. This is suggestive of a probable dissociation between speech and other expressive forms of communication, indicating an isolated speech production impairment. This highlights a need in this population for alternative communication and specific input from services tailored to support the nuances of the communication profile of Angelman syndrome.
WHAT THIS PAPER ADDS
Although absent speech is near universal, a diverse profile of other communicative abilities has been reported. Parental reporting has been predominantly used to assess the communication profile of Angelman syndrome. Literature that investigates the specificities and possible dissociations in such a communication profile is limited.
Topics: Angelman Syndrome; Communication; Humans; Nonverbal Communication; Speech
PubMed: 31074506
DOI: 10.1111/dmcn.14257 -
Genetics in Medicine : Official Journal... Feb 2023Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the...
PURPOSE
Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified.
METHODS
Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes.
RESULTS
In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect.
CONCLUSION
HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.
Topics: Humans; Angelman Syndrome; Ubiquitin; Ubiquitin-Protein Ligases; Neurodevelopmental Disorders; Phenotype
PubMed: 36401616
DOI: 10.1016/j.gim.2022.10.006 -
Journal of Communication Disorders 2022Objective evaluation of receptive communication abilities in nonspeaking individuals using standardized behavioral measures can be complicated by co-occurring...
INTRODUCTION
Objective evaluation of receptive communication abilities in nonspeaking individuals using standardized behavioral measures can be complicated by co-occurring intellectual disabilities and motor difficulties. Eye tracking during listening may offer an informative complementary approach to directly evaluate receptive language skills.
METHOD
This study examined feasibility of eye gaze measures as an index of spoken language comprehension in nonspeaking children and adults with Angelman syndrome (AS; n = 23) using a looking-while-listening procedure. Typically developing children (n = 34) provided a reference data set. Primary caregivers of participants with AS completed standardized informant reports (MacArthur-Bates Communicative Development Inventory: Words and Gestures; Vineland Adaptive Behavior Scales-3; Aberrant Behavior Checklist-2) to characterize communicative skills and general adaptive functioning.
RESULTS
Gaze data in participants with AS, particularly in the individuals reported by caregivers to have larger receptive vocabularies and stronger adaptive communicative functioning, demonstrated the expected pattern of comprehension reflected by the increased probability of looks to the target images after vs. before they were named in a spoken sentence. However, processing speed (gaze reaction time) was significantly slower in participants with AS than in the typically developing group.
CONCLUSIONS
Gaze-based paradigms could be an informative measure of receptive communication processes in participants who are unable to complete traditional standardized behavioral assessments.
Topics: Child; Adult; Humans; Comprehension; Angelman Syndrome; Vocabulary; Language; Gestures
PubMed: 36244082
DOI: 10.1016/j.jcomdis.2022.106272 -
Revista de Neurologia Apr 2023Angelman syndrome (AS) is widely described in childhood, but few studies have been conducted in adulthood and most of them report a small number of patients or specific...
INTRODUCTION
Angelman syndrome (AS) is widely described in childhood, but few studies have been conducted in adulthood and most of them report a small number of patients or specific conditions, such as epilepsy or sleep.
AIM
The aim of this study is to describe AS in adulthood in our centre, the special needs it requires, and the medical and social support to improve care and to provide a better transition from the paediatric service to units for adults.
PATIENTS AND METHODS
We collected patients with genetically confirmed AS, and described demographic, medical and social data by reviewing medical records, telephone interviews with the primary caregiver and three standardised sleep, dependency and quality of life scales.
RESULTS
Thirty patients with a median age of 22.7 years were included: 22 were deletions, 27 had a history of epilepsy and 13 were on treatment involving at least two antiepileptic drugs. The most frequent comorbidities after epilepsy were psychiatric symptoms, scoliosis, overweight, constipation and ophthalmological problems. Forty per cent required hospital admissions in adulthood, five were institutionalised and 24 received non-medical therapies. The doctor in charge was the neurologist in most cases, followed by the neuropaediatrician.
CONCLUSIONS
Studies that examine the natural history beyond childhood are warranted. This is the first Spanish review of adults with AS that covers a broad spectrum of social and medical conditions of these patients.
Topics: Adult; Child; Humans; Young Adult; Angelman Syndrome; Quality of Life; Epilepsy; Mental Disorders; Comorbidity
PubMed: 36973885
DOI: 10.33588/rn.7607.2022235 -
Journal of Neurodevelopmental Disorders Nov 2023The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes in chromosome 15 (Angelman...
OBJECTIVE
The objective of this study was to identify the age of diagnosis for children with one of three neurogenetic conditions resulting from changes in chromosome 15 (Angelman syndrome [AS], Prader-Willi syndrome [PWS], and duplication 15q syndrome [Dup15q]).
METHODS
Data about the diagnostic process for each condition were contributed by the advocacy organizations. Median and interquartile ranges were calculated for each condition by molecular subtype and year. Comparison tests were run to explore group differences.
RESULTS
The median age of diagnosis was 1.8 years for both AS and Dup15q. PWS was diagnosed significantly younger at a median age of 1 month. Deletion subtypes for both PWS and AS were diagnosed earlier than nondeletion subtypes, and children with isodicentric duplications in Dup15q were diagnosed earlier than those with interstitial duplications.
CONCLUSION
Understanding variability in the age of diagnosis for chromosome 15 disorders is an important step in reducing the diagnostic odyssey and improving access to interventions for these populations. Results from this study provide a baseline by which to evaluate efforts to reduce the age of diagnosis for individuals with these conditions.
Topics: Humans; Child; Infant; Prader-Willi Syndrome; Chromosome Disorders; Chromosomes; Angelman Syndrome; Trisomy
PubMed: 37936142
DOI: 10.1186/s11689-023-09504-x -
Journal of Neurodevelopmental Disorders Mar 2024Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems,...
BACKGROUND
Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems, emotional/behavioral challenges, and a tendency towards hyperphagia and weight gain. The characteristics of AS make it difficult to measure these children's functioning with standard clinical tests. Feasible outcome measures are needed to measure current functioning and change over time, in clinical practice and clinical trials.
AIM
Our first aim is to assess the feasibility of several functional tests. We target domains of neurocognitive functioning and physical growth using the following measurement methods: eye-tracking, functional Near-Infrared Spectroscopy (fNIRS), indirect calorimetry, bio-impedance analysis (BIA), and BOD POD (air-displacement plethysmography). Our second aim is to explore the results of the above measures, in order to better understand the AS phenotype.
METHODS
The study sample consisted of 28 children with AS aged 2-18 years. We defined an outcome measure as feasible when (1) at least 70% of participants successfully finished the measurement and (2) at least 60% of those participants had acceptable data quality. Adaptations to the test procedure and reasons for early termination were noted. Parents rated acceptability and importance and were invited to make recommendations to increase feasibility. The results of the measures were explored.
RESULTS
Outcome measures obtained with eye-tracking and BOD POD met the definition of feasibility, while fNIRS, indirect calorimetry, and BIA did not. The most important reasons for early termination of measurements were showing signs of protest, inability to sit still and poor/no calibration (eye-tracking specific). Post-calibration was often applied to obtain valid eye-tracking results. Parents rated the BOD POD als most acceptable and fNIRS as least acceptable for their child. All outcome measures were rated to be important. Exploratory results indicated longer reaction times to high salient visual stimuli (eye-tracking) as well as high body fat percentage (BOD POD).
CONCLUSIONS
Eye-tracking and BOD POD are feasible measurement methods for children with AS. Eye-tracking was successfully used to assess visual orienting functions in the current study and (with some practical adaptations) can potentially be used to assess other outcomes as well. BOD POD was successfully used to examine body composition.
TRIAL REGISTRATION
Registered d.d. 23-04-2020 under number 'NL8550' in the Dutch Trial Register: https://onderzoekmetmensen.nl/en/trial/23075.
Topics: Child; Humans; Angelman Syndrome; Reproducibility of Results; Body Composition; Plethysmography; Electric Impedance
PubMed: 38429713
DOI: 10.1186/s11689-024-09516-1 -
Neurobiology of Disease Feb 2018Epilepsy is prevalent and often medically intractable in Angelman syndrome (AS). AS mouse model (Ube3a) shows reduced excitatory neurotransmission but lower seizure...
Epilepsy is prevalent and often medically intractable in Angelman syndrome (AS). AS mouse model (Ube3a) shows reduced excitatory neurotransmission but lower seizure threshold. The neural mechanism linking the synaptic dysfunction to the seizure remains elusive. We show that the local circuits of Ube3ain vitro are hyperexcitable and display a unique epileptiform activity, a phenomenon that is reminiscent of the finding in fragile X syndrome (FXS) mouse model. Similar to the FXS model, lovastatin suppressed the epileptiform activity and audiogenic seizures in Ube3a. The in vitro model of Ube3a is valuable for dissection of neural mechanism and epilepsy drug screening in vivo.
Topics: Angelman Syndrome; Animals; Anticonvulsants; Disease Models, Animal; Epilepsy; Female; Hippocampus; Lovastatin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Culture Techniques; Seizures; Ubiquitin-Protein Ligases
PubMed: 29097328
DOI: 10.1016/j.nbd.2017.10.016 -
American Journal of Medical Genetics.... Jul 2023Angelman Syndrome is a rare neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, characteristic behavior,...
Angelman Syndrome is a rare neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, characteristic behavior, and movement disorders. Clinical gait analysis provides the opportunity for movement quantification to investigate an observed maladaptive change in gait pattern and offers an objective outcome of change. Pressure-sensor-based technology, inertial and activity monitoring, and instrumented gait analysis (IGA) were employed to define motor abnormalities in Angelman syndrome. Temporal-spatial gait parameters of persons with Angelman Syndrome (pwAS) show deficiencies in gait performance through walking speed, step length, step width, and walk ratio. pwAS walk with reduced step lengths, increased step width, and greater variability. Three-dimensional motion kinematics showed increased anterior pelvic tilt, hip flexion, and knee flexion. PwAS have a walk ratio more than two standard deviations below controls. Dynamic electromyography showed prolonged activation of knee extensors, which was associated with a decreased range of motion and the presence of hip flexion contractures. Use of multiple gait tracking modalities revealed that pwAS exhibit a change in gait pattern to a flexed knee gait pattern. Cross-sectional studies of individuals with AS show a regression toward this maladaptive gait pattern over development in pwAS ages 4-11. PwAS unexpectedly did not have spasticity associated with change in gait pattern. Multiple quantitative measures of motor patterning may offer early biomarkers of gait decline consistent with critical periods of intervention, insight into appropriate management strategies, objective primary outcomes, and early indicators of adverse events.
Topics: Humans; Angelman Syndrome; Cross-Sectional Studies; Walking; Gait; Knee Joint; Biomechanical Phenomena
PubMed: 37019838
DOI: 10.1002/ajmg.a.63192