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Neuroscience Oct 2020The UBE3A gene is part of the chromosome 15q11-q13 region that is frequently deleted or duplicated, leading to several neurodevelopmental disorders (NDD). Angelman... (Review)
Review
The UBE3A gene is part of the chromosome 15q11-q13 region that is frequently deleted or duplicated, leading to several neurodevelopmental disorders (NDD). Angelman syndrome (AS) is caused by the absence of functional maternally derived UBE3A protein, while the paternal UBE3A gene is present but silenced specifically in neurons. Patients with AS present with severe neurodevelopmental delay, with pronounced motor deficits, absence of speech, intellectual disability, epilepsy, and sleep problems. The pathophysiology of AS is still unclear and a treatment is lacking. Animal models of AS recapitulate the genotypic and phenotypic features observed in AS patients, and have been invaluable for understanding the disease process as well as identifying apropriate drug targets. Using these AS mouse models we have learned that loss of UBE3A probably affects many areas of the brain, leading to increased neuronal excitability and a loss of synaptic spines, along with changes in a number of distinct behaviours. Inducible AS mouse models have helped to identify the critical treatment windows for the behavioral and physiological phenotypes. Additionally, AS mouse models indicate an important role for the predominantly nuclear UBE3A isoform in generating the characteristic AS pathology. Last, but not least, the AS mice have been crucial in guiding Ube3a gene reactivation treatments, which present a very promising therapy to treat AS.
Topics: Angelman Syndrome; Animals; Disease Models, Animal; Humans; Male; Mice; Neurons; Phenotype; Ubiquitin-Protein Ligases
PubMed: 32088294
DOI: 10.1016/j.neuroscience.2020.02.017 -
International Journal of Molecular... Sep 2021Angelman-like syndromes are a group of neurodevelopmental disorders that entail clinical presentation similar to Angelman Syndrome (AS). In our previous study, we showed...
Angelman-like syndromes are a group of neurodevelopmental disorders that entail clinical presentation similar to Angelman Syndrome (AS). In our previous study, we showed that calcium signaling is disrupted in AS, and we identified calcium-target and calcium-regulating gene signatures that are able to differentiate between AS and their controls in different models. In the herein study, we evaluated these sets of calcium-target and calcium-regulating genes as signatures of AS-like and non-AS-like syndromes. We collected a number of RNA-seq datasets of various AS-like and non-AS-like syndromes and performed Principle Component Analysis (PCA) separately on the two sets of signature genes to visualize the distribution of samples on the PC1-PC2 plane. In addition to the evaluation of calcium signature genes, we performed differential gene expression analyses to identify calcium-related genes dysregulated in each of the studied syndromes. These analyses showed that the calcium-target and calcium-regulating signatures differentiate well between AS-like syndromes and their controls. However, in spite of the fact that many of the non-AS-like syndromes have multiple differentially expressed calcium-related genes, the calcium signatures were not efficient classifiers for non-AS-like neurodevelopmental disorders. These results show that features based on clinical presentation are reflected in signatures derived from bioinformatics analyses and suggest the use of bioinformatics as a tool for classification.
Topics: Angelman Syndrome; Calcium; Calcium Signaling; Chromosome Deletion; Computational Biology; Gene Expression Regulation; Humans; Principal Component Analysis; RNA-Seq
PubMed: 34576033
DOI: 10.3390/ijms22189870 -
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 -
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 -
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 -
Molecular Therapy : the Journal of the... Apr 2023Angelman syndrome (AS) is a neurogenetic disorder caused by the loss of ubiquitin ligase E3A (UBE3A) gene expression in the brain. The UBE3A gene is paternally imprinted...
Angelman syndrome (AS) is a neurogenetic disorder caused by the loss of ubiquitin ligase E3A (UBE3A) gene expression in the brain. The UBE3A gene is paternally imprinted in brain neurons. Clinical features of AS are primarily due to the loss of maternally expressed UBE3A in the brain. A healthy copy of paternal UBE3A is present in the brain but is silenced by a long non-coding antisense transcript (UBE3A-ATS). Here, we demonstrate that an artificial transcription factor (ATF-S1K) can silence Ube3a-ATS in an adult mouse model of Angelman syndrome (AS) and restore endogenous physiological expression of paternal Ube3a. A single injection of adeno-associated virus (AAV) expressing ATF-S1K (AAV-S1K) into the tail vein enabled whole-brain transduction and restored UBE3A protein in neurons to ∼25% of wild-type protein. The ATF-S1K treatment was highly specific to the target site with no detectable inflammatory response 5 weeks after AAV-S1K administration. AAV-S1K treatment of AS mice showed behavioral rescue in exploratory locomotion, a task involving gross and fine motor abilities, similar to low ambulation and velocity in AS patients. The specificity and tolerability of a single injection of AAV-S1K therapy for AS demonstrate the use of ATFs as a promising translational approach for AS.
Topics: Animals; Mice; Angelman Syndrome; Brain; Gene Expression Regulation; Transcription Factors; Phenotype; Ubiquitin-Protein Ligases
PubMed: 36641623
DOI: 10.1016/j.ymthe.2023.01.013 -
Pharmaceutics Nov 2022Antisense oligonucleotides (ASOs) are disease-modifying agents affecting protein-coding and noncoding ribonucleic acids. Depending on the chemical modification and the... (Review)
Review
Antisense oligonucleotides (ASOs) are disease-modifying agents affecting protein-coding and noncoding ribonucleic acids. Depending on the chemical modification and the location of hybridization, ASOs are able to reduce the level of toxic proteins, increase the level of functional protein, or modify the structure of impaired protein to improve function. There are multiple challenges in delivering ASOs to their site of action. Chemical modifications in the phosphodiester bond, nucleotide sugar, and nucleobase can increase structural thermodynamic stability and prevent ASO degradation. Furthermore, different particles, including viral vectors, conjugated peptides, conjugated antibodies, and nanocarriers, may improve ASO delivery. To date, six ASOs have been approved by the US Food and Drug Administration (FDA) in three neurological disorders: spinal muscular atrophy, Duchenne muscular dystrophy, and polyneuropathy caused by hereditary transthyretin amyloidosis. Ongoing preclinical and clinical studies are assessing the safety and efficacy of ASOs in multiple genetic and acquired neurological conditions. The current review provides an update on underlying mechanisms, design, chemical modifications, and delivery of ASOs. The administration of FDA-approved ASOs in neurological disorders is described, and current evidence on the safety and efficacy of ASOs in other neurological conditions, including pediatric neurological disorders, is reviewed.
PubMed: 36365206
DOI: 10.3390/pharmaceutics14112389 -
Autism Research : Official Journal of... Jan 2020Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by mutation or deletion of the maternally inherited UBE3A allele. These pathogenic mutations lead to... (Review)
Review
Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by mutation or deletion of the maternally inherited UBE3A allele. These pathogenic mutations lead to loss of maternal UBE3A expression in neurons. Antisense oligonucleotides and gene therapies are in development, which activate the intact but epigenetically silenced paternal UBE3A allele. Preclinical studies indicate that treating during the prenatal period could greatly reduce the severity of symptoms or prevent AS from developing. Genetic tests can detect the chromosome 15q11-q13 deletion that is the most common cause of AS. New, highly sensitive noninvasive prenatal tests that take advantage of single-cell genome sequencing technologies are expected to enter the clinic in the coming years and make early genetic diagnosis of AS more common. Efforts are needed to identify fetuses and newborns with maternal 15q11-q13 deletions and to phenotype these babies relative to neurotypical controls. Clinical and parent observations suggest AS symptoms are detectable in infants, including reports of problems with feeding and motor function. Quantitative phenotypes in the 0- to 1-year age range will permit a more rapid assessment of efficacy when future treatments are administered prenatally or shortly after birth. Although prenatal therapies are currently not available for AS, prenatal testing combined with prenatal treatment has the potential to revolutionize how clinicians detect and treat babies before they are symptomatic. This pioneering prenatal treatment path for AS will lay the foundation for treating other syndromic neurodevelopmental disorders. Autism Res 2020, 13: 11-17. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Prenatal treatment could benefit expectant parents whose babies test positive for the chromosome microdeletion that causes Angelman syndrome (AS). Prenatal treatment is predicted to have better outcomes than treating after symptoms develop and may even prevent AS altogether. This approach could generally be applied to the treatment of other syndromic neurodevelopmental disorders.
Topics: Angelman Syndrome; Female; Genetic Testing; Genetic Therapy; Humans; Neurodevelopmental Disorders; Pregnancy; Prenatal Diagnosis
PubMed: 31490639
DOI: 10.1002/aur.2203