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Progress in Neurobiology Nov 2023Angelman Syndrome (AS) is a severe cognitive disorder caused by loss of neuronal expression of the E3 ubiquitin ligase UBE3A. In an AS mouse model, we previously...
Angelman Syndrome (AS) is a severe cognitive disorder caused by loss of neuronal expression of the E3 ubiquitin ligase UBE3A. In an AS mouse model, we previously reported a deficit in brain-derived neurotrophic factor (BDNF) signaling, and set out to develop a therapeutic that would restore normal signaling. We demonstrate that CN2097, a peptidomimetic compound that binds postsynaptic density protein-95 (PSD-95), a TrkB associated scaffolding protein, mitigates deficits in PLC-CaMKII and PI3K/mTOR pathways to restore synaptic plasticity and learning. Administration of CN2097 facilitated long-term potentiation (LTP) and corrected paired-pulse ratio. As the BDNF-mTORC1 pathway is critical for inhibition of autophagy, we investigated whether autophagy was disrupted in AS mice. We found aberrantly high autophagic activity attributable to a concomitant decrease in mTORC1 signaling, resulting in decreased levels of synaptic proteins, including Synapsin-1 and Shank3. CN2097 increased mTORC1 activity to normalize autophagy and restore hippocampal synaptic protein levels. Importantly, treatment mitigated cognitive and motor dysfunction. These findings support the use of neurotrophic therapeutics as a valuable approach for treating AS pathology.
Topics: Animals; Mice; Angelman Syndrome; Brain-Derived Neurotrophic Factor; Hippocampus; Long-Term Potentiation; Mechanistic Target of Rapamycin Complex 1; Microfilament Proteins; Nerve Tissue Proteins; Peptidomimetics; Transcription Factors
PubMed: 37536482
DOI: 10.1016/j.pneurobio.2023.102513 -
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 -
Oncotarget Jun 2015
Topics: Angelman Syndrome; Animals; Cerebellum; Male; Motor Skills; Multiprotein Complexes; TOR Serine-Threonine Kinases
PubMed: 26116835
DOI: 10.18632/oncotarget.4298 -
Neurotherapeutics : the Journal of the... Jul 2021Angelman syndrome (AS) is a rare (~1:15,000) neurodevelopmental disorder characterized by severe developmental delay and intellectual disability, impaired communication... (Review)
Review
Angelman syndrome (AS) is a rare (~1:15,000) neurodevelopmental disorder characterized by severe developmental delay and intellectual disability, impaired communication skills, and a high prevalence of seizures, sleep disturbances, ataxia, motor deficits, and microcephaly. AS is caused by loss-of-function of the maternally inherited UBE3A gene. UBE3A is located on chromosome 15q11-13 and is biallelically expressed throughout the body but only maternally expressed in the brain due to an RNA antisense transcript that silences the paternal copy. There is currently no cure for AS, but advancements in small molecule drugs and gene therapies offer a promising approach for the treatment of the disorder. Here, we review AS and how loss-of-function of the maternal UBE3A contributes to the disorder. We also discuss the strengths and limitations of current animal models of AS. Furthermore, we examine potential small molecule drug and gene therapies for the treatment of AS and associated challenges faced by the therapeutic design. Finally, gene therapy offers the opportunity for precision medicine in AS and advancements in the treatment of this disorder can serve as a foundation for other single-gene neurodevelopmental disorders.
Topics: Angelman Syndrome; Animals; Anticonvulsants; Biological Products; Genetic Therapy; Humans; Isoxazoles; Neurodevelopmental Disorders; RNA, Antisense; Recombinant Fusion Proteins; Ubiquitin-Protein Ligases
PubMed: 34528170
DOI: 10.1007/s13311-021-01082-x -
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 -
Clinical Anatomy (New York, N.Y.) Jul 2016Angelman's syndrome (AS) is a genetic neurodevelopment disorder. The cause is a known abnormality involving the maternal inherited ubiquitin-protein ligase (UBE3A) gene.... (Review)
Review
Angelman's syndrome (AS) is a genetic neurodevelopment disorder. The cause is a known abnormality involving the maternal inherited ubiquitin-protein ligase (UBE3A) gene. Clinical characteristics universal to the disorder are well documented in the literature and include developmental delay, seizures, ataxia, altered tone, severely impaired speech and intellect, as well as an overall happy demeanor, frequent bouts of laughter, and hypermotoric behavior. Associated with this disorder are several musculoskeletal aberrations. To date, a review of case studies reporting on these musculoskeletal changes has not been carried out. Thus, the purpose of this paper was to provide an overview of the musculoskeletal changes present in individuals with AS. In our review of 21 case reports from 1965-2013, the most consistently reported anatomical changes were of the craniofacial region. These include microcephaly, brachycephaly, a palpable occipital groove, prognathism, and wide spaced teeth. Other musculoskeletal abnormalities less frequently reported in the literature include scoliosis, excessive lumbar lordosis, and pes planus. Given that the majority of the case reports reviewed was of young children, the possibility of underreporting musculoskeletal changes which may manifest in the later years of life may be present. Early diagnosis and interventions to minimize secondary complications are crucial to maintain quality of life. An overall multidisciplinary approach is emphasized to maximize developmental potential for these individuals. Future prospective studies that follow patients into adulthood are needed to better understand the prevalence and development of secondary musculoskeletal changes, which in turn can inform intervention techniques and preventative measures. Clin. Anat. 29:561-567, 2016. © 2015 Wiley Periodicals, Inc.
Topics: Angelman Syndrome; Diagnosis, Differential; Disease Management; Humans; Musculoskeletal Abnormalities; Prevalence; Prognosis; Skull
PubMed: 26480021
DOI: 10.1002/ca.22659 -
Journal of Intellectual Disability... Oct 2019Anxiety is considered a 'frequent' feature in the clinical criteria for Angelman syndrome; however, the nature and severity of anxiety symptoms have not been well...
BACKGROUND
Anxiety is considered a 'frequent' feature in the clinical criteria for Angelman syndrome; however, the nature and severity of anxiety symptoms have not been well characterised in this population. Anxiety behaviours, especially in response to separation from a preferred caregiver, have been described clinically but have not yet been explored empirically.
METHOD
This study used a combination of standardised and clinician-derived survey items to assess the frequency, nature and severity of behaviours associated with anxiety and separation distress in 100 individuals with Angelman syndrome. Family (e.g. income and maternal education) and individual (e.g. age, sex, genetic subtype, sleep difficulties and aggressive behaviours) variables were also gathered to assess possible predictors of higher anxiety levels. Approximately half of the sample was seen in clinic and assessed with standardised measures of development and daily functioning, allowing for an additional exploration of the association between anxiety symptoms and extent of cognitive impairment.
RESULTS
Anxiety concerns were reported in 40% of the sample, almost 70% were reported to have a preferred caregiver and over half displayed distress when separated from that caregiver. Individuals with the deletion subtype and individuals who are younger were less likely to have anxiety behaviours. Sleep difficulties and aggressive behaviour consistently significantly predicted total anxiety, the latter suggesting a need for future studies to tease apart differences between anxiety and aggression or anger in this population.
CONCLUSIONS
Anxiety concerns, especially separation distress, are common in individuals with Angelman syndrome and represent an area of unmet need for this population.
Topics: Adolescent; Adult; Angelman Syndrome; Anxiety; Anxiety, Separation; Caregivers; Child; Child, Preschool; Female; Humans; Infant; Male; Middle Aged; Object Attachment; Parent-Child Relations; Parents; Psychological Distress; Young Adult
PubMed: 31134691
DOI: 10.1111/jir.12635 -
Special Care in Dentistry : Official... Nov 2020To analyze the mineralization and ion content in deciduous, permanent teeth of Angelman syndrome in comparison to match-paired teeth from normal children.
AIMS
To analyze the mineralization and ion content in deciduous, permanent teeth of Angelman syndrome in comparison to match-paired teeth from normal children.
METHODS
Three deciduous teeth and a third molar and a mesiodens extracted during routine dental treatment and their match-paired normal teeth were examined using energy dispersive X-ray spectrometer program under a scanning electron microscope.
RESULTS
The morphology of the enamel and dentin of Angelman syndrome (AS) teeth was similar to normal but the thickness of the enamel of deciduous canine and permanent teeth was reduced. The most marked differences were found in the enamel-in AS teeth, the enamel contained nitrogen in concentrations similar to dentin, implicating that the protein content of the enamel is different from normal teeth where nitrogen is absent.
CONCLUSIONS
AS affects morphology and mineralization of enamel. It caused hypoplastic enamel and abnormal protein content in comparison to match-paired normal teeth. These findings show that AS also affects odontogenesis in addition to the known oral motor challenges.
Topics: Angelman Syndrome; Child; Dental Enamel; Dentin; Dentition, Permanent; Humans; Tooth
PubMed: 32881030
DOI: 10.1111/scd.12514