Hypothesis-free DNA methylation profiling in a 66-year-old male with unexplained neurodevelopmental disorder enabled the exclusion of ZNF142-related disease (left panel) and led to a retrospective diagnosis of Angelman syndrome, highlighting the diagnostic potential of single-patient epigenetic screening (right panel).

3p Deletion syndrome is a rare genetic disorder characterized by intellectual disability, growth delay, hypotonia, and distinctive facial features, with considerable phenotypic variability. Previous reports have highlighted the significance of deletions within the 3p25.3 region contributing to the development of Angelman-like features, such as stereotypic movements, a happy demeanor, epilepsy, and characteristic electroencephalogram (EEG) patterns. This study analyzed 22 patients of 3p deletion syndrome, focusing on epilepsy and EEG findings. A newly defined short smallest region of overlap (sSRO) within 3p25.3, encompassing approximately 52 kb and partially including SLC6A1 and SLC6A11, was associated with Angelman-like features, particularly epilepsy and EEG patterns. Patients with sSRO deletions exhibited a high incidence of seizures (60 %), characterized by myoclonic or absence seizures, with EEG showing generalized high-amplitude slow waves. In contrast, larger deletions beyond the sSRO were linked to dysmorphological features of 3p-syndrome, generalized tonic-clonic seizure, and non-specific EEG findings. These findings suggest that SLC6A1 dysfunction contributes to epilepsy and EEG abnormalities, possibly via impaired GABA transport, whereas patients with larger or non-overlapping deletions exhibited more typical 3p-syndrome features, suggesting that multiple neurological genes in the broader deletion region may independently contribute to more severe neurological phenotypes. In conclusion, it is important to consider GABA-related disorders, including a specific chromosomal abnormality known as 3p-syndrome with a microdeletion in the SRO region, when observing characteristic epilepsy and EEG findings resembling Angelman syndrome.

Neurodevelopment is an intricate process with highly regulated, overlapping stages including neuronal differentiation and axon guidance. Aberrations during these and other stages are tied to the etiology of neurodevelopmental disorders like Autism Spectrum Disorder, Angelman Syndrome, and X-linked Intellectual Disability. Ubiquitination is a dynamic and highly reversible post-translational modification conferred by E3 ubiquitin ligases. Recent discoveries have advanced the understanding of how substrate ubiquitination can guide protein localization, drive protein degradation, and alter protein post translational modifications. In this review, we highlight members of the RING and HECT E3 ligase families to discuss their novel roles in the molecular mechanisms regulating neurodevelopment. These findings are both instrumental for informing the future directions of neurodevelopmental research, and in expanding knowledge of intracellular mechanisms of protein trafficking. In addition, a deeper understanding of the molecular mechanisms of E3 ligase function in development promises to offer new insights into the pathogenesis of neurodevelopmental disorders.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are rare imprinting disorders caused by the aberrant expression of 15q11.2-q13 imprinted genes. Due to their rarity, data on health outcomes during infancy are limited. This EUROlinkCAT study aimed to investigate major health outcomes of children with these chromosomal disorders. Data of children born in 1995-2014 and diagnosed with PWS (n=150) or AS (n=46), collected by 11 population-based congenital anomaly registries, were linked to local electronic healthcare and mortality databases and analysed. Children with PWS had a survival rate of 94% (95% CI 89.5% to 98.7%) by 10 years of age. Nearly all children (99.5%, 95% CI 97.6% to 99.9%) with PWS required hospitalisation during the first year of life with a median length of stay of 25 days; a high proportion continued to need hospital care later in life (93.2% at 1-4 years and 79.6% at 5-9 years) with shorter stays (1.2 and 0.5 days per year, respectively). In comparison, no deaths occurred among children with AS by 10 years of age. Fewer children with AS required hospitalisation in the first year of life (59.0%, 95% CI 39.6% to 74.0%); as they grew older, the proportion admitted was 68% (95% CI 40.0% to 85.0%) at 5-9 years. Children with PWS and AS underwent first surgery at approximately 1.8 years and 2.5 years, respectively. This study provides valuable evidence for improving family counselling and promoting an adequate healthcare support system.

Pediatric vomiting and feeding difficulties are common presentations in both emergency and outpatient settings. Although these symptoms are often attributed to benign causes such as infections or gastroenteritis, structural and functional esophageal disorders must also be considered. This report describes two diagnostically challenging cases of esophageal obstruction in children. The first involves a 10-year-old boy with Angelman syndrome, ultimately diagnosed with a double aortic arch causing extrinsic esophageal compression. The second case features a previously healthy 13-year-old with chronic vomiting, later identified as having primary achalasia. These cases highlight the importance of maintaining a broad differential diagnosis and employing targeted imaging to prevent delays in diagnosis.

The Bayley Scales of Infant and Toddler Development- 4th Edition (Bayley-4) and Vineland Adaptive Behavior Scales - 3rd Edition (Vineland-3) are outcome measures often considered as primary endpoints in clinical trials for Angelman syndrome (AS). We explored barriers encountered when administering these instruments to individuals with AS and associated guidance for their use in trials and research studies. We interviewed nine clinicians who have administered the Bayley-4 and/or the Vineland-3 to individuals with AS and analyzed their transcripts using a quasi-deductive analysis approach. Barriers to administering the Bayley-4 included participant's lack of interest, overexcitement, emotional impact on caregiver, the mental workload of administering the Bayley-4, and environmental factors (e.g., administration setting). Barriers to administering the Vineland-3 included determining the most appropriate start point, emotional impact on caregiver, distractions, conflicting answers from two caregivers, and the mental workload of administering the Vineland-3. Participants provided potential solutions to each barrier. Lastly, we identified overarching item-level concerns for both the Bayley-4 (i.e., administration challenges, items not aligned with abilities) and the Vineland-3 (i.e., misalignment of assessment criteria and condition characteristics, limitations in observation and contextual understanding, requires specialized training). Clinical trials often rely on the Bayley-4 and Vineland-3 assessments as outcome measures, yet our identified barriers threaten their validity. The associated solutions provide a path forward for improving administration of the Bayley-4 and Vineland-3 in clinical practice, research, and future trials focused on individuals with AS and other intellectual and developmental disabilities.

A person with Angelman syndrome (AS), a rare neurogenetic condition that significantly affects health and daily functioning, needs lifetime specialized care. Consequently, parents of individuals with AS experience decreased quality of life, high levels of parental stress and burden, and severe financial strain. This study analyses the experiences of Polish parents of persons with AS. Gender differences between mothers and fathers are also reported, and the association between financial well-being, caregiving burden, and quality of life is evaluated. A self-administered, anonymous, computer-assisted online survey on parents' caregiving experiences was conducted among 119 parents associated with the Association of Families with Angelman Syndrome and FAST Poland-Foundation for Angelman Syndrome Therapeutics between March and August 2024. Although both mothers and fathers of those with AS experience parental strain resulting from caregiving, decreased quality of life, and financial well-being, mothers experienced higher levels of caregiving burden (P = 0.004). It was also observed that the physical health of mothers and parents of children with delayed diagnoses was more affected by the caregiving. Financial well-being was the only factor significantly associated with both decreased quality of life in all domains and increased levels of caregiver burden. To improve the quality of life of parents of those with AS, financial assistance, psychological counseling, emotional support, and respite care programs are needed. Simultaneously, although such interventions should include gender differences, they should focus on more burdened mothers. Financial assistance is the most required resource that may enhance parents' life satisfaction and health-related quality of life.

Angelman syndrome is a neurodevelopmental disorder caused by (epi)genetic lesions of maternal UBE3A. Research has focused largely on the role of UBE3A in neurons due to its imprinting in that cell type. Yet, evidence suggests there may be broader neurodevelopmental impacts of UBE3A dysregulation. Human cerebral organoids might reveal these understudied aspects of UBE3A as they recapitulate diverse cell types of the developing human brain. In this study, scRNAseq on organoids reveals the effects of UBE3A disruption on cell type-specific compositions and transcriptomic alterations. In the absence of UBE3A, progenitor proliferation and structures are disrupted while organoid composition shifts away from proliferative cell types. We observe impacts on non-neuronal cells, including choroid plexus enrichment. Furthermore, EMX1+ cortical progenitors are negatively impacted; potentially disrupting corticogenesis and delaying excitatory neuron maturation. This work reveals impacts of UBE3A on understudied cell types and related neurodevelopmental processes and elucidates potential therapeutic targets.

Hexasomy of the Prader-Willi/Angelman Syndrome Critical Region (PWASCR; chromosome 15q11-q13) is very rare with only 13 patients being described to date. The region is known for its high susceptibility to genomic rearrangements, and extra copies within the region have been shown to be associated with distinct but variable clinical features of intellectual disability, epilepsy, global developmental delay amongst others. We present a 10-year-old girl with moderate to severe intellectual disability, cerebral palsy, seizures, autistic features and challenging behaviours. Her karyotype is 47,XX,+mar[25]/46,XX[5]. On chromosome analysis using G-banding, we identified a very large dicentric supernumerary marker chromosome 15q11-q13. Microarray analysis and metaphase fluorescence in-situ hybridisation using the SNRPN gene specific to 15q11.2-q13.3 region showed 87 % of cells containing 6 signals and 13 % of cells containing 2 signals. This represents mosaicism for a partial hexasomy of the long arm of chromosome 15q. We also reviewed and consolidated the literature of all reported patients with hexasomy of PWASCR, and found that amongst all 14 patients (including ours), despite some variation in phenotype, all patients had seizures, and the majority had intellectual disability and challenging behaviours.

Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe developmental delay, speech impairment, ataxia and happy demeanor. AS is caused by loss-of-function of maternal UBE3A in neurons due to (epi)genetic abnormalities. Here, we report two new induced pluripotent stem cell (iPSC) lines from male and female patients carrying ∼ 6 Mb deletions in chr15q11.2-q13.1, together with familial control iPSC lines. All lines express pluripotent stem cell markers, demonstrate trilineage differentiation, and maintain genetic and epigenetic integrity at the locus of interest. These iPSCs provide a platform to model class I deletions, the most severe AS cause, and accelerate therapy development.

We describe the development and validation of PANDABox-EEG, a novel protocol for remote EEG assessment with no on-site technician, tailored for Angelman syndrome (AS). We argue that this protocol is reliable, valid, and widely acceptable for use in families affected by Angelman syndrome. AS is a rare neurogenetic condition characterized by developmental delays, sleep problems, seizures, and a happy demeanor. People with AS are frequently monitored via EEG to inform clinical care, and EEG-measured delta activity has been proposed as a reliable biomarker to monitor treatment effectiveness. Traditional EEG assessments pose logistical and financial burdens for families due to the need to travel to a medical center to complete assessments. Telehealth methods, however, offer a pathway forward. PANDABox-EEG was developed through multidisciplinary collaboration with psychologists, psychophysiologists, engineers, and special-education scholars, incorporating caregiver feedback and user-centered design principles. It pairs PANDABox, a telehealth platform for biobehavioral assessment in rare disorders, with a dry electrode EEG system. Twenty-eight participants (7 AS, 7 siblings, 14 caregivers) completed three 5-min EEG sessions each over the course of a week. Caregivers were asked to provide feedback on acceptability of the design, and EEG data was quantified and assessed for metrics of reliability and validity. PANDABox-EEG demonstrated high feasibility and acceptability, with 91% of caregivers reporting strong satisfaction assessment comfort. EEG data quality was promising, with high internal consistency (split-half reliability range for children with AS: r = .96-.98) and test-retest reliability for delta power among (test-retest reliability range for children with AS: ρ = .88-.96). Finally, we successfully detected the characteristic increased delta power in AS (effect size between AS and non-AS siblings: d = 1.56-2.85) and its association with age (effect size between non-AS siblings and caregivers: d = 2.19-2.72). PANDABox-EEG provides a feasible, cost-effective, and reliable method for remote EEG assessment in AS. Its high caregiver satisfaction and ability to capture relevant neurophysiological markers suggest potential for broader application. With further validation, PANDABox-EEG can enhance accessibility and inclusivity, benefiting clinical management and research in AS and other clinical populations in need of frequent EEG monitoring by eliminating the need to travel.

Loss of production of ubiquitin protein ligase E3A (UBE3A) in neurons leads to Angelman Syndrome (AS). There are limited methods to reliably measure UBE3A in cerebrospinal fluid (CSF), which negatively impacts therapeutic development. To overcome this gap, we developed and analytically validated a novel method for CSF UBE3A quantitation, which includes an immunoprecipitation protein capture step followed by tryptic digestion and high-resolution mass spectrometry detection of a unique UBE3A peptide. Our data suggest that we can reliably detect UBE3A at concentrations as low as 2.5 pg/mL. The assay was used to show that UBE3A could be detected in CSF samples of both healthy adults and patients with AS. As expected, CSF UBE3A levels in healthy adults (24.76 ± 6.75 pg/mL, N = 14) were significantly higher (p < 0.01) than the CSF UBE3A levels measured in two AS cohorts (5.30 ± 0.42 pg/mL, N = 19 and 5.59 ± 0.40 pg/mL, N = 10), with no significant difference in UBE3A levels observed between the two AS cohorts. There was also no significant difference in CSF UBE3A levels when comparing AS patients carrying either a mutation or chromosomal deletion in either cohort. Overall, these data demonstrate the utility of this novel CSF UBE3A assay for UBE3A quantitation in studies of AS.

Neurological disorders, ranging from common conditions like Alzheimer's disease that is a progressive neurodegenerative disorder and remains the most common cause of dementia worldwide to rare disorders such as Angelman syndrome, impose a significant global health burden. Altered facial expressions are a common symptom across these disorders, potentially serving as a diagnostic indicator. Deep learning algorithms, especially convolutional neural networks (CNNs), have shown promise in detecting these facial expression changes, aiding in diagnosing and monitoring neurological conditions. This systematic review and meta-analysis aimed to evaluate the performance of deep learning algorithms in detecting facial expression changes for diagnosing neurological disorders. Following PRISMA2020 guidelines, we systematically searched PubMed, Scopus, and Web of Science for studies published up to August 2024. Data from 28 studies were extracted, and the quality was assessed using the JBI checklist. A meta-analysis was performed to calculate pooled accuracy estimates. Subgroup analyses were conducted based on neurological disorders, and heterogeneity was evaluated using the I statistic. The meta-analysis included 24 studies from 2019 to 2024, with neurological conditions such as dementia, Bell's palsy, ALS, and Parkinson's disease assessed. The overall pooled accuracy was 89.25% (95% CI 88.75-89.73%). High accuracy was found for dementia (99%) and Bell's palsy (93.7%), while conditions such as ALS and stroke had lower accuracy (73.2%). Deep learning models, particularly CNNs, show strong potential in detecting facial expression changes for neurological disorders. However, further work is needed to standardize data sets and improve model robustness for motor-related conditions.

Angelman syndrome (AS) is a developmental disorder caused by one of four molecular etiologies. Affected individuals have intellectual disability (ID), limited speech, seizures, and sleep problems. Parents of individuals with AS exhibit elevated stress compared to parents of individuals with other IDs. We examined parental stress and family quality of life (FQOL) over time in families of individuals living with AS. Data were collected in a natural history study of AS. The Parenting Stress Index, Third Edition (PSI) and the Beach Center FQOL scale assessed parent stress and FQOL. Stress and FQOL were examined across AS molecular subtypes, and predictors were analyzed using a generalised linear model. Relationships between parental stress and FQOL were examined using Pearson correlations and a stepwise mixed-linear model approach. Our sample consisted of 231 families of individuals living with AS. Parental stress was clinically elevated and was highest in families of individuals with mutations, while FQOL did not differ across subtype in most domains. Increasing age predicted a decrease in parental stress but did not predict FQOL. Elevated parental stress was additionally predicted by maladaptive behaviours and child male sex, while lower FQOL was predicted by child male sex, parent marital status, and family income. Parental stress had a small negative impact on FQOL. Stress is elevated in parents of individuals with AS across subtypes and has a small negative impact on family quality of life. Interventions to reduce stress have potential to improve individual and family well-being.

Translational research is needed to discover pharmacological targets and treatments for the diagnostic behavioral domains of neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASDs) and intellectual disabilities (IDs). One NDD, associated with ASD and ID, is Angelman Syndrome (AS). AS is a rare genetic NDD for which there is currently no cure nor effective therapeutics. The genetic cause is known to be the loss of expression from the maternal allele of ubiquitin protein ligase E3A (UBE3A). The Ube3a maternal deletion mouse model of AS reliably demonstrates behavioral phenotypes of relevance to AS and therefore offers a suitable in vivo system in which to test potential therapeutics, with construct and face validity. Successes in reducing hyperexcitability and epileptogenesis have been reported in an AS model following acute treatment with lovastatin, an ERK inhibitor by reducing seizure threshold and percentage of mice exhibiting seizures. Since there has been literature reporting disruption of the ERK signaling pathway in AS, we chose to evaluate the effects of acute lovastatin administration in a tailored set of translationally relevant behavioral assays in a mouse model of AS. Unexpectedly, deleterious effects of sedation were observed in wildtype (WT), age matched littermate control mice and despite a baseline hypolocomotive phenotype in AS mice, even further reductions in exploratory activity, were observed post-acute lovastatin treatment. Limitations of this work include that chronic lower dose regimens, more akin to drug administration in humans were beyond the scope of this work, and may have produced a more favorable impact of lovastatin administration over single acute high doses. In addition, lovastatin's effects were not assessed in younger subjects, since our study focused exclusively on adult functional outcomes. Metrics of gait, as well as motor coordination and motor learning in rotarod, previously observed to be impaired in AS mice, were not improved by lovastatin treatment. Finally, cognition by novel object recognition task was worsened in WT controls and not improved in AS, following lovastatin administration. In conclusion, lovastatin did not indicate any major improvement to AS symptoms, and in fact, worsened behavioral outcomes in the WT control groups. Therefore, despite its attractive low toxicity, immediate availability, and low cost of the drug, further investigation for clinical study is unwarranted given the results presented herein.

A literature review of the current state of the etiology and pathogenesis of genomic imprinting disorders such as Angelman syndrome and Prader-Willi syndrome was performed. The mechanisms of the development of sleep disorders associated with these syndromes related to impaired expression of specific genes are considered in detail. The article focuses on modern sleep disorder treatment methods in Angelman and Prader-Willi syndromes and shows their effectiveness and prospects for use in clinical practice. Проведен анализ литературы современных представлений об этиологии и патогенезе таких заболеваний геномного импринтинга, как синдромы Ангельмана и Прадера—Вилли. Подробно рассмотрены механизмы развития расстройств сна, которые сопутствуют синдромам, на фоне нарушения экспрессии определенных генов. Особое внимание в статье уделено современным методам терапии нарушений сна при синдромах Ангельмана и Прадера—Вилли, показаны их эффективность и перспективность использования в клинической практике.

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, a sociable demeanor, and abnormal movements. People with AS often exhibit multiple types of abnormal movements, including nonepileptic myoclonus, tremor, and dystonia, which hamper attempts to identify phenomenology and appropriate treatments. We sought to better clarify movement disorder phenomenology in AS to aid in diagnostic clarity and treatment identification. Caregivers of people with AS completed a survey focused on abnormal movements in AS and submitted video examples of the movements, when possible. The video data were evaluated by a team of 10 movement disorder experts. Survey data were obtained for 47 subjects, of whom 20 had accompanying video data; 33% of subjects reported 3 or more abnormal movements, complicating the evaluation of the survey data. Expert review of video data demonstrated 9 people with myoclonus, 9 with dystonia, and 3 with tremor. Five people had both myoclonus and dystonia, and 1 had both tremor and dystonia. Three people demonstrated stereotypy, one of which also had a focal seizure. Dystonia onset averaged 18.1 years. Fever, constipation, and menses were the most notable triggers. According to caregivers, only 4 treatments, clonazepam, diazepam, lorazepam, and trihexyphenidyl, resulted in improvement in dystonic symptoms. These data reinforce that dystonia is a common finding in people with AS, often in combination with myoclonus. The identification of both isolated dystonia and myoclonic dystonia in people with AS may suggest therapeutic options that heretofore may not have been widely considered.

The loss of maternal UBE3A causes Angelman syndrome whereas its duplication is associated with a heterogeneous neurodevelopmental disorder. Here, we describe two affected brothers who possess a novel UBE3A variant that is not present in two neurotypical siblings. The UBE3A variant was confirmed to be maternally inherited, and the affected individuals exhibited early global developmental delay, ongoing learning difficulties, and autistic features. Their phenotypes were inconsistent with Angelman syndrome. Biochemical characterization showed the UBE3A variant causes a dramatic increase in the activity of the UBE3A enzyme, suggesting that a gain in UBE3A activity is the driver of neurodevelopmental disease. Our observations document an emerging class of neurodevelopmental disorders caused by gain-of-function mutations in UBE3A.

This case report describes a 39-year-old phenotypically normal male patient of a married couple with primary infertility presenting as candidates for assisted reproductive techniques. The medical history of the couple is unremarkable, with both partners phenotypically normal. Semen analysis revealed oligoasthenzoospermia (OAT), 15% sperm DNA fragmentation and 4% aneuploidies in the sperm nuclei. Genetic analysis showed no Y chromosome of cystic fibrosis transmembrane conductance regulator gene mutations. Karyotype analysis in the male partner revealed a small supernumerary marker chromosome (sSMC) derived from chromosome 15, specifically inverted and duplicated (inv dup(15)) corresponding to the 15q11.2 region but lacking the Prader-Willi/Angelman syndrome critical region (PWACR). Further investigations revealed that 35% of the patient's spermatozoa carried the sSMC(15). This case study highlights the potential association between the presence of an inv dup(15) sSMC, without the involvement of the PWACR, and male infertility. sSMC(15) may disrupt spermatogenesis and contribute to oligoasthenozoospermia in males with primary infertility. Further research into the association of mechanism mechanisms of male infertility related to the 15q11.2 region is warranted.

Angelman syndrome (AS) is a severe neurological disorder characterized by intellectual disability, absence of speech, spontaneous seizure, and motor dysfunction. The absence of functional maternally derived UBE3A protein is considered the primary cause of AS, yet the downstream signaling pathways remain elusive. Here, we show the voltage-gated K channel Kv4.2 as an activity-dependent substrate for UBE3A. We show that UBE3A binding of Kv4.2 at its N terminus, ubiquitinating residue K103, induces activity-induced Kv4.2 protein loss. In a mouse model of AS, we observe elevated Kv4.2 protein level and abolished kainic acid-induced Kv4.2 protein loss. Moreover, deficits in mEPSC frequency and spike-timing-dependent long-term potentiation, as well as certain behaviors including cognitive inflexibility found in AS mice, are rescued when bred with Kv4.2 conditional knockout mice. These findings indicate a UBE3A downstream pathway regulating plasticity and cognitive behaviors and provide potential targets for the treatment of AS.