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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 -
Biomolecules Dec 2023Variants in the gene, which encodes the β subunit of the GABA receptor, have been implicated in various epileptic encephalopathies and related neurodevelopmental...
Variants in the gene, which encodes the β subunit of the GABA receptor, have been implicated in various epileptic encephalopathies and related neurodevelopmental disorders such as Dravet syndrome and Angelman syndrome. These conditions are often associated with early-onset seizures, developmental regression, and cognitive impairments. The severity and specific features of these encephalopathies can differ based on the nature of the genetic variant and its impact on GABA receptor function. These variants can lead to dysfunction in GABA receptor-mediated inhibition, resulting in an imbalance between neuronal excitation and inhibition that contributes to the development of seizures. Here, 13 EE-associated variants, occurring as missense mutations, were analyzed to determine their impact on protein stability and flexibility, channel function, and receptor biogenesis. Our results showed that all mutations studied significantly impact the protein structure, altering protein stability, flexibility, and function to varying degrees. Variants mapped to the GABA-binding domain, coupling zone, and pore domain significantly impact the protein structure, modifying the β+/α- interface of the receptor and altering channel activation and receptor trafficking. Our study proposes that the extent of loss or gain of GABA receptor function can be elucidated by identifying the specific structural domain impacted by mutation and assessing the variability in receptor structural dynamics. This paves the way for future studies to explore and uncover links between the incidence of a variant in the receptor topology and the severity of the related disease.
Topics: Humans; Receptors, GABA-A; Mutation, Missense; Mutation; Seizures; Brain Diseases
PubMed: 38136660
DOI: 10.3390/biom13121790 -
Developmental Medicine and Child... Jul 2024To investigate parents' preferences and motivations for receiving and discussing prognostic genetic test results.
AIM
To investigate parents' preferences and motivations for receiving and discussing prognostic genetic test results.
METHOD
We used a cross-sectional, interpretive description qualitative study design. We collected data through semi-structured interviews with Australian parents, which we analysed using reflexive thematic analysis.
RESULTS
Parents (n = 32) had a child or children with a genetic neurodevelopmental condition, such as fragile X syndrome, DiGeorge (22q11.2 deletion) syndrome, or Angelman syndrome. Parents of mildly impacted or older children were tolerant to prognostic uncertainty. Parents found conversations about their child's prognosis emotional and preferred to discuss their child's potential strengths and challenges. While most were enthusiastic about prognostic tests and described many motivations for testing, the potential for prognostic information to contribute to a loss of hope and stigmatizing societal views were also discussed.
INTERPRETATION
Parents had mixed preferences and motivations for acquiring prognostic genetic information about their child, contrasting evidence in other contexts such as cancer where parents typically have minimal tolerance of uncertainty. Health professionals should consider strength-based framing of prognostic information gained from current and emerging technologies when returning results to families.
WHAT THIS PAPER ADDS
Parents had varied views about receiving prognostic information on their children's neurodevelopmental condition. Some parents preferred prognostic uncertainty about their children's genetic neurodevelopmental condition.
Topics: Humans; Parents; Male; Female; Qualitative Research; Child; Prognosis; Adult; Neurodevelopmental Disorders; Cross-Sectional Studies; Adolescent; Genetic Testing; Child, Preschool; Australia; Middle Aged
PubMed: 38111102
DOI: 10.1111/dmcn.15830 -
Gene Mar 2024Azadiradione is a small bioactive limonoid found in the seed of Azadirachta Indica, an Indian medicinal plant commonly known as Neem. Recently, it has been shown to...
Azadiradione is a small bioactive limonoid found in the seed of Azadirachta Indica, an Indian medicinal plant commonly known as Neem. Recently, it has been shown to ameliorate the disease pathology in fly and mouse model of Huntington's disease by restoring impaired proteostasis. Here we report that the azadiradione could be involved in modulating the synaptic function through increased expression of Ube3a, a dual function protein having ubiquitin ligase and co-activator functions and associated with Angelman syndrome and autism. Treatment of azadiradione to HT22 hippocampal cell line and in adult mice induced the expression of Ube3a as well as two important synaptic function and plasticity regulating proteins, parvalbumin and brain-derived neurotropic factor (BDNF). Interestingly, another synaptic plasticity modulating protein Arc (activity-regulated cytoskeletal associated protein) was down-regulated by azadiradione. Partial knockdown of Ube3a in HT22 cell abrogated azadiradione induced expression of parvalbumin and BDNF. Ube3a-maternal deficient mice also exhibited significantly decreased expression of parvalbumin and BDNF in their brain and treatment of azadiradione in these animals did not rescue the altered expression of either parvalbumin or BDNF. These results indicate that azadiradione-induced expression of parvalbumin and BDNF in the brain is mediated through Ube3a and suggest that azadiradione could be implicated in restoring synaptic dysfunction in many neuropsychiatric/neurodegenerative disorders.
Topics: Mice; Animals; Limonins; Brain-Derived Neurotrophic Factor; Parvalbumins; Ubiquitin-Protein Ligases; Brain; Angelman Syndrome; Disease Models, Animal
PubMed: 38101713
DOI: 10.1016/j.gene.2023.148081 -
Journal of Intellectual Disability... Mar 2024Angelman syndrome (AS) is a rare neurodevelopmental disorder characterised by severe intellectual disability, movement disorder, epilepsy, sleeping problems, and...
BACKGROUND
Angelman syndrome (AS) is a rare neurodevelopmental disorder characterised by severe intellectual disability, movement disorder, epilepsy, sleeping problems, and behavioural issues. Little is known on child health-related quality of life (HRQoL) in AS. AS family studies have reported elevated parenting stress and a high impact of the child's syndrome on the parent. It is unclear which factors influence child HRQoL and parenting stress/impact in AS.
METHODS
We collected data prospectively through standardised clinical assessments of children with AS at the ENCORE Expertise centre for Angelman Syndrome at the Erasmus MC Sophia Children's Hospital. A linear regression analysis was conducted for the following outcome variables: (1) child HRQoL (Infant and Toddler Quality of Life Questionnaire); (2) the impact of the child's syndrome on the parent (Infant and Toddler Quality of Life Questionnaire); and (3) parenting stress (Parenting Stress Index). Predictor variables were child genotype, epilepsy, sleeping problems (Sleep Disturbance Scale for Children), cognitive developmental level (Bayley Cognition Scale), autistic features (Autism Diagnostic Observation Schedule) and emotional/behavioural problems (Child Behaviour Checklist). Covariates were sex, age and socio-economic status.
RESULTS
The study sample consisted of 73 children with AS, mean age = 9.1 years, range = 2-18 years. Emotional/behavioural problems were the strongest significant predictor of lowered child HRQoL. Internalising problems were driving this effect. In addition, having the deletion genotype and higher age was related to lower child HRQoL. Sleeping problems were related to a higher impact of the child's syndrome on the parent. Finally, emotional/behavioural problems were associated with higher parenting stress. Cognitive developmental level, autistic features and epilepsy were not a significant predictor of child HRQoL and parenting stress/impact.
CONCLUSIONS
These results suggest that interventions aimed at increasing child HRQoL and decreasing parenting stress/impact in AS should focus on child emotional/behavioural problems and sleeping problems, using a family-centred approach.
Topics: Infant; Humans; Child, Preschool; Child; Adolescent; Parenting; Quality of Life; Angelman Syndrome; Epilepsy; Sleep Wake Disorders
PubMed: 38009976
DOI: 10.1111/jir.13106 -
Japanese Journal of Ophthalmology Jan 2024To investigate the relationship between the details of strabismus and orbital abnormalities determined by ocular motility tests and orbital imaging examinations in 9...
PURPOSE
To investigate the relationship between the details of strabismus and orbital abnormalities determined by ocular motility tests and orbital imaging examinations in 9 cases with Angelman syndrome (AS).
STUDY DESIGN
A retrospective, clinical report.
METHODS
The 9 AS cases (mean age at initial visit: 4.6 ± 8.0 years) were confirmed by genetic diagnosis of the chromosome 15q11-13 region. In all cases, axial imaging of the orbit in the transverse plane of the horizontal extraocular muscles was obtained. The opening angle between both lateral walls of the orbit (greater wing of sphenoid) was measured as the biorbital angle, and compared with the 95% confidence interval of the orbital angle in normal children.
RESULTS
All cases had exotropia with means of the distance and near of angle 32.2 prism diopters (Δ) ± 9.7Δ and 32.8Δ ± 8.3Δ. The mean of the biorbital angle was 107.7° ± 7.6°, greater than the biorbital angle of 94.3° ± 5.1° previously reported in 129 normal children (P < 0.0001, t-test). Except for one biorbital angle of 93° in the 25-year-old patient, all the biorbital angles in the 8 children were larger than the upper 95% confidence interval in normal children. Astigmatic and hyperopic ametropic amblyopia were detected in 3 cases and 1 case, respectively.
CONCLUSIONS
The frequency of exotropia in AS is higher than previously reported, with our results strongly suggesting that the enlarged biorbital angle is related to the pathogenesis of exotropia in AS.
Topics: Child; Humans; Child, Preschool; Adult; Exotropia; Angelman Syndrome; Retrospective Studies; Strabismus; Oculomotor Muscles; Orbital Diseases; Ophthalmologic Surgical Procedures
PubMed: 38006466
DOI: 10.1007/s10384-023-01030-6 -
Antioxidants (Basel, Switzerland) Nov 2023The article presents a review of the relationships between melatonin and neurodevelopmental disorders. First, the antioxidant properties of melatonin and its... (Review)
Review
The article presents a review of the relationships between melatonin and neurodevelopmental disorders. First, the antioxidant properties of melatonin and its physiological effects are considered to understand better the role of melatonin in typical and atypical neurodevelopment. Then, several neurodevelopmental disorders occurring during infancy, such as autism spectrum disorder or neurogenetic disorders associated with autism (including Smith-Magenis syndrome, Angelman syndrome, Rett's syndrome, Tuberous sclerosis, or Williams-Beuren syndrome) and neurodevelopmental disorders occurring later in adulthood like bipolar disorder and schizophrenia, are discussed with regard to impaired melatonin production and circadian rhythms, in particular, sleep-wake rhythms. This article addresses the issue of overlapping symptoms that are commonly observed within these different mental conditions and debates the role of abnormal melatonin production and altered circadian rhythms in the pathophysiology and behavioral expression of these neurodevelopmental disorders.
PubMed: 38001870
DOI: 10.3390/antiox12112017 -
Journal of Neurochemistry Dec 2023Angelman syndrome, a severe neurodevelopmental disorder, is primarily caused by mutations or deletions of maternally inherited ubiquitin protein ligase E3A (UBE3A)....
Angelman syndrome, a severe neurodevelopmental disorder, is primarily caused by mutations or deletions of maternally inherited ubiquitin protein ligase E3A (UBE3A). Activation of the silenced paternal copy of UBE3A can occur with pharmacological perturbation; however, an environmental approach has not been examined. Here, we found Ube3a is highly expressed in embryonic and early neonatal mouse retina and is maternally-, but not paternally-, expressed in ganglion cells, amacrine cells, and horizontal cells. Moreover, we analyzed UBE3A expression in the retina and visual cortex of postnatal day 28 mice (P28) following exposure to light emissions from white compact-fluorescent bulbs or blue light-emitting diodes from postnatal day 0 (P0) to 28 (P28), encompassing a crucial phase of visual system development. We found higher levels of Ube3a RNA and protein in the retina, but not visual cortex compared with tissues from P28 mice exposure to typical lighting (controls). Levels of both paternal- and maternal-UBE3A protein in mouse retina were higher than controls in P28 mice exposed to white or blue light. Moreover, levels of open and repressive chromatin structures, indicated by histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 27 trimethylation (H3K27me3), respectively, were increased in the Ube3a promoter from mouse retina exposed to white or blue light. Our findings strongly suggest that extended exposure to white or blue light constitutes a substantial environmental factor that can effectively promote UBE3A expression within the central nervous system.
Topics: Mice; Animals; Angelman Syndrome; Histones; Chromatin; Lysine; Retina; Ubiquitin-Protein Ligases
PubMed: 37994169
DOI: 10.1111/jnc.16018 -
European Journal of Paediatric... Nov 2023
PubMed: 37989651
DOI: 10.1016/j.ejpn.2023.11.008 -
International Journal of Molecular... Oct 2023The impact of segmental duplications on human evolution and disease is only just starting to unfold, thanks to advancements in sequencing technologies that allow for...
The impact of segmental duplications on human evolution and disease is only just starting to unfold, thanks to advancements in sequencing technologies that allow for their discovery and precise genotyping. The 15q11-q13 locus is a hotspot of recurrent copy number variation associated with Prader-Willi/Angelman syndromes, developmental delay, autism, and epilepsy and is mediated by complex segmental duplications, many of which arose recently during evolution. To gain insight into the instability of this region, we characterized its architecture in human and nonhuman primates, reconstructing the evolutionary history of five different inversions that rearranged the region in different species primarily by accumulation of segmental duplications. Comparative analysis of human and nonhuman primate duplication structures suggests a human-specific gain of directly oriented duplications in the regions flanking the cores and segmental duplications, representing potential genomic drivers for the human-specific expansions. The increasing complexity of segmental duplication organization over the course of evolution underlies its association with human susceptibility to recurrent disease-associated rearrangements.
Topics: Animals; Humans; DNA Copy Number Variations; Primates; Prader-Willi Syndrome; Segmental Duplications, Genomic; Autistic Disorder; Chromosomes, Human, Pair 15; Gene Duplication
PubMed: 37958807
DOI: 10.3390/ijms242115818