-
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 -
Journal of Clinical Medicine Sep 2023Angelman Syndrome (AS) is a rare genetic disorder caused by lack of maternal UBE3A protein due to a deletion of the chromosome 15q11.2-q13 region, uniparental paternal...
Angelman Syndrome (AS) is a rare genetic disorder caused by lack of maternal UBE3A protein due to a deletion of the chromosome 15q11.2-q13 region, uniparental paternal disomy, imprinting center defect, or pathogenic variant in the gene. Characteristics are developmental delay, epilepsy, behavioral, and sleep problems. There is some evidence for hyperphagia, shorter stature, and higher BMI compared to neurotypical children, but longitudinal studies on growth are lacking. In this study, we analyzed prospectively collected data of 145 children with AS, who visited the ENCORE Expertise Center between 2010 and 2021, with a total of 853 visits. Children showed an elevated mean score of 25 on the Dykens Hyperphagia questionnaire (range 11-55) without genotype association. Higher scores were significantly associated with higher body mass index (BMI) standard deviation scores (SDS) ( = 0.004). Mean height was -1.2 SDS (SD 1.3), mean BMI-SDS was 0.6 (SD 1.7); 43% had a BMI-SDS > 1 and 20% had a BMI-SDS > 2. Higher BMI-SDS was significantly associated with non-deletion genotype ( = 0.037) and walking independently ( = 0.023). Height SDS decreased significantly with age ( < 0.001) and BMI-SDS increased significantly with age ( < 0.001. Onset of puberty was normal. In conclusion, children with AS showed moderate hyperphagia, lower height SDS, and higher BMI-SDS compared to norm data, with increasing deviation from the norm with age. It is uncertain how loss of maternal UBE3A function may influence growth. Attention to diet, exercise, and hyperphagia from an early age is recommended to prevent obesity and associated health problems.
PubMed: 37762921
DOI: 10.3390/jcm12185981 -
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 -
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 -
Sleep Medicine Sep 2019Cataplexy is a transient loss of muscle tone that can be triggered by emotions such as laughter, excitement or fear. Other causes of cataplexy include Niemann-Pick type... (Review)
Review
Cataplexy is a transient loss of muscle tone that can be triggered by emotions such as laughter, excitement or fear. Other causes of cataplexy include Niemann-Pick type C Disease, Angelman Syndrome, Norrie Disease, Prader-Willi Syndrome. In addition, cataplexy can be a side effect of several drugs (eg, lamotrigine, clozapine, and gamma-hydroxybutyrate). Yet, the most prevalent causes of cataplexy without narcolepsy are rare genetic diseases; which explains why cataplexy is classically linked to narcolepsy. Therefore, it is essential disconnecting cataplexy from narcolepsy especially in pediatric population and after use of a few medications. In this review, we described few conditions of cataplexy not related to narcolepsy. We performed a review of literature (MEDLINE and EMBASE database), without limited date or publication restrictions.
Topics: Cataplexy; Humans; Narcolepsy
PubMed: 31427075
DOI: 10.1016/j.sleep.2019.03.006 -
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 -
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