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In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1–2 % of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found.

Angelman syndrome (AS) is a neurodevelopmental disorder in which epilepsy is common (~90%) and often refractory to antiepileptics. AS is caused by mutation of the maternal allele encoding the ubiquitin protein ligase E3A (UBE3A), but it is unclear how this genetic insult confers vulnerability to seizure development and progression (i.e., epileptogenesis). Here, we implemented the flurothyl kindling and retest paradigm in AS model mice to assess epileptogenesis and to gain mechanistic insights owed to loss of maternal Ube3a. AS model mice kindled similarly to wild-type mice, but they displayed a markedly increased sensitivity to flurothyl-, kainic acid-, and hyperthermia-induced seizures measured a month later during retest. Pathological characterization revealed enhanced deposition of perineuronal nets in the dentate gyrus of the hippocampus of AS mice in the absence of overt neuronal loss or mossy fiber sprouting. This pro-epileptogenic phenotype resulted from Ube3a deletion in GABAergic but not glutamatergic neurons, and it was rescued by pancellular reinstatement of Ube3a at postnatal day 21 (P21), but not during adulthood. Our results suggest that epileptogenic susceptibility in AS patients is a consequence of the dysfunctional development of GABAergic circuits, which may be amenable to therapies leveraging juvenile reinstatement of UBE3A.

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder with profoundly debilitating symptoms with no FDA-approved cure or therapeutic. Brain-derived neurotrophic factor (BDNF), and its receptor tropomyosin receptor kinase B (TrkB), have a well-established role as regulators of synaptic plasticity, dendritic outgrowth and spine formation. Previously, we reported that the association of postsynaptic density protein 95 (PSD-95) with TrkB is critical for intact BDNF signaling in the AS mouse model, as illustrated by attenuated PLCγ and PI3K signaling and intact MAPK pathway signaling. These data suggest that drugs tailored to enhance the TrkB-PSD-95 interaction may provide a novel approach for the treatment of AS and a variety of neurodevelopmental disorders (NDDs). To evaluate this critical interaction, we synthesized a class of high-affinity PSD-95 ligands that bind specifically to the PDZ3 domain of PSD-95, denoted as Syn3 peptidomimetic ligands. We evaluated Syn3 and its analog D-Syn3 (engineered using dextrorotary (D)-amino acids) in vivo using the Ube3a exon 2 deletion mouse model of AS. Following systemic administration of Syn3 and D-Syn3, we demonstrate improvement in the seizure domain of AS. Learning and memory using the novel object recognition assay also illustrated improved cognition following Syn3 and D-Syn3, along with restored long-term potentiation. A pharmacokinetic analysis of D-Syn3 demonstrates that it crosses the blood-brain barrier (BBB), and the brain influx rate is in the range of CNS therapeutics. Finally, D-Syn3 treated mice showed a partial rescue in motor learning. Neither Syn3 nor D-Syn3 improved gross exploratory locomotion deficits, nor gait impairments that have been well documented in the AS rodent models. These findings highlight the need for further investigation of this compound class as a potential therapeutic for AS and other genetic NDDs.

We describe the development of 236 children with Angelman syndrome (AS) using the Bayley Scales of Infant and Toddler Development, Third Edition. Multilevel linear mixed modeling approaches were used to explore differences between molecular subtypes and over time. Individuals with AS continue to make slow gains in development through at least age 12 years of age at about 1–2 months/year based on age equivalent score and 1–16 growth score points/year depending on molecular subtype and domain. Children with a deletion have lower scores at baseline and slower rate of gaining skills while children with UBE3A variant subtype demonstrated higher scores as well as greater rates of skill attainment in all domains. The developmental profiles of UPD and ImpD were similar.

Background Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence‐based literature. We present a consensus statement and comprehensive literature review that proposes a standard of care practices for the management of AS at a critical time when therapeutics to alter the natural history of the disease are on the horizon. Methods We compiled the key recognized clinical features of AS based on consensus from a team of specialists managing patients with AS. Working groups were established to address each focus area with committees comprised of providers who manage >5 individuals. Committees developed management guidelines for their area of expertise. These were compiled into a final document to provide a framework for standardizing management. Evidence from the medical literature was also comprehensively reviewed. Results Areas covered by working groups in the consensus document include genetics, developmental medicine, psychology, general health concerns, neurology (including movement disorders), sleep, psychiatry, orthopedics, ophthalmology, communication, early intervention and therapies, and caregiver health. Working groups created frameworks, including flowcharts and tables, to help with quick access for providers. Data from the literature were incorporated to ensure providers had review of experiential versus evidence‐based care guidelines. Conclusion Standards of care in the management of AS are keys to ensure optimal care at a critical time when new disease‐modifying therapies are emerging. This document is a framework for providers of all familiarity levels.

Angelman syndrome is a neurodevelopmental disorder caused by disrupted function of the maternal copy of the imprinted UBE3A gene; here, targeting a long non-coding RNA that is responsible for silencing the paternal copy of UBE3A with antisense oligonucleotides is shown to partially restore UBE3A expression in the central nervous system and correct some cognitive deficits in a mouse model of the disease. Therapy for Angelman syndrome Frank Rigo and colleagues report the development of the first gene-specific therapy for Angelman syndrome, a severe neurodevelopmental disorder caused by disrupted function of the maternal copy of the imprinted gene UBE3A. The paternal copy of UBE3A is intact but silenced by a long non-coding RNA antisense transcript, UBE3A-ATS . The authors show that by reducing Ube3a-ATS with antisense oligonucleotides (ASOs), the silencing of paternal Ube3a can be reversed in cultured mouse neurons and in vivo . Some phenotypes in an Angelman syndrome mouse model, including obesity and memory impairment can also be corrected. Angelman syndrome is a single-gene disorder characterized by intellectual disability, developmental delay, behavioural uniqueness, speech impairment, seizures and ataxia 1 , 2 . It is caused by maternal deficiency of the imprinted gene UBE3A , encoding an E3 ubiquitin ligase 3 , 4 , 5 . All patients carry at least one copy of paternal UBE3A , which is intact but silenced by a nuclear-localized long non-coding RNA, UBE3A antisense transcript ( UBE3A-ATS ) 6 , 7 , 8 . Murine Ube3a-ATS reduction by either transcription termination or topoisomerase I inhibition has been shown to increase paternal Ube3a expression 9 , 10 . Despite a clear understanding of the disease-causing event in Angelman syndrome and the potential to harness the intact paternal allele to correct the disease, no gene-specific treatment exists for patients. Here we developed a potential therapeutic intervention for Angelman syndrome by reducing Ube3a-ATS with antisense oligonucleotides (ASOs). ASO treatment achieved specific reduction of Ube3a-ATS and sustained unsilencing of paternal Ube3a in neurons in vitro and in vivo . Partial restoration of UBE3A protein in an Angelman syndrome mouse model ameliorated some cognitive deficits associated with the disease. Although additional studies of phenotypic correction are needed, we have developed a sequence-specific and clinically feasible method to activate expression of the paternal Ube3a allele.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are imprinting disorders caused by genetic or epigenetic aberrations of 15q11.2-q13. Their clinical testing is often multitiered; diagnostic testing begins with methylation-specific multiplex ligation-dependent probe amplification or methylation-sensitive PCR and then proceeds to molecular subtyping to determine the mechanism and recurrence risk. Currently, correct classification of a proband’s PWS/AS subtype often requires parental samples, a costly process for families and health systems. The use of nanopore sequencing for molecular diagnosis of PWS and AS has been explored by Yamada et al; however, to confirm heterodisomy parental data were still required. Here, we investigate genome-wide nanopore sequencing in a larger cohort of PWS (18) and AS (6) as a singular test to detect the molecular subtype, without parental data. We accurately subtyped these cases including uniparental heterodisomy, mixed iso-/heterodisomy, type 1 and 2 deletions, microdeletion and UBE3A indels. One PWS case with a previously unresolved diagnosis subtyped as maternal isodisomy. This work highlights the application of long-read sequencing and other imprinted regions outside of the PWS/AS critical region to resolve the molecular diagnosis and subtyping of PWS and AS without parental data. The work also outlines an approach to generically detect heterodisomy through the interrogation of distant imprinted regions.

In the current study, we examined adaptive skills and trajectories over time in 257 individuals with Angelman syndrome (AS) using the Vineland Adaptive Behavior Scales, 2nd Edition. Multilevel linear models were used to examine differences between molecular subtypes over time, from one year to 13 years of age, in the adaptive domains of communication, daily living skills, socialization and motor skills. Individuals with non-deletion subtypes typically demonstrated a higher level of adaptive skills compared to those with deletion subtypes. Statistically significant growth was observed in all adaptive domains through at least early adolescence. Individuals with AS should continue to receive developmental services and educational supports through adolescence and into adulthood given the slow rates of growth being observed across adaptive domains.

Aims This study aims to identify the prevalence and risk factors of dysphagia in a Chinese cohort of Angelman syndrome (AS). Methods A structured questionnaire was used to assess the status of patients in a Chinese cohort of AS. Swallowing function was evaluated using the Pediatric Eating Assessment Tool‐10, with gastrointestinal symptoms quantified via the Six‐item Gastrointestinal Severity Index (6‐GSI). To identify potential risk factors, univariable and multivariate logistic regression was performed. Results Among 490 patients with AS (median 6 years, interquartile range 4 years), the molecular subtypes of 75.7% of cases were deletions of 15q11–q13. The prevalence of dysphagia reached 56.1%. Patients with dysphagia exhibited lower BMI values compared to nondysphagia cases (15.31 ± 2.87 vs. 15.92 ± 2.91 kg/m2, p = 0.021). Multivariate logistic regression analysis identified that uniparental paternal disomy (UPD) was associated with lower odds of dysphagia compared with deletions of 15q11–q13 (OR = 0.34, p = 0.016). Comorbid sleep disorders (OR = 1.79, p = 0.007), gastrointestinal disorders (OR = 1.89, p = 0.003), and increased 6‐GSI scores (OR = 1.16, p = 0.044) showed associations with higher odds of dysphagia. Conclusions Over half of Chinese patients with AS experience dysphagia, with UPD moderating risk and comorbidities amplifying susceptibility. In Chinese cohort of Angelman syndrome (AS), the prevalence of dysphagia reached 56.1%, with uniparental paternal disomy associated with lower odds of dysphagia. Comorbid sleep disorders and gastrointestinal disorders, as well as higher scores on 6‐GSI, were linked to increased odds of dysphagia.

Background The objective of this study is to describe healthcare resource utilization (HRU) and supportive therapy utilization (STU) among individuals with Angelman syndrome (AS), and to compare such usage by molecular etiology. Methods Participants were categorized into deletion and non‐deletion genotypes. Statistical differences were assessed using an independent samples t test. Results Data were available on 302 individuals. Mean age of participants was 5.5 years, 92% of whom were less than 13 years, and 71% had the deletion etiology. About 68% of participants had at least one hospitalization since birth to enrollment in the study; the average number of hospitalizations during that time period was 2.3 and average length of stay was 4.5 days. The most common reasons for hospitalization were seizures, lower respiratory infections, and surgery. The most common reasons for surgery were myringotomy, strabismus surgery, tonsillectomy or adenoidectomy, and gastrostomy tube insertion/fundoplication. Anticonvulsants, gastroesophageal reflux disease, sleep, and behavioral medications were the most commonly prescribed drugs. STU was high among individuals with AS. Conclusions This study shows that individuals with AS have high HRU/STU, and apart from a few differences, HRU/STU was similar across molecular etiology. These results reflect usage in younger individuals and studies that describe HRU/STU in older individuals are needed. The objective of this study is to describe healthcare resource utilization (HRU) and supportive therapy utilization (STU) among individuals with Angelman syndrome (AS). Results from this study suggest that individuals with AS have high HRU/STU, and apart from a few differences, HRU/STU was similar across molecular etiologies.