Angelman Research Articles

Protein Accumulation and Impaired Autophagy Underlie Cognitive Dysfunction in Angelman Syndrome

Angelman syndrome (AS) is a genetic neurodevelopmental disorder that is accompanied by several neurological impairments including cognitive and intellectual disabilities, seizures, developmental delay, and others ( 1 Bird L.M. Angelman syndrome: Review of clinical and molecular aspects. Appl Clin Genet. 2014; 7: 93-104 Crossref PubMed Scopus (147) Google Scholar ). How the genetic abnormalities that cause AS result in these brain-related impairments remains unknown. Emerging work has revealed that AS is associated with elevated levels of activity-regulated cytoskeletal protein (ARC), which is an immediate-early gene (IEG) product that plays a critical role in driving learning-related synaptic plasticity ( 2 Pastuzyn E.D. Shepherd J.D. Activity-dependent arc expression and homeostatic synaptic plasticity are altered in neurons from a mouse model of Angelman syndrome. Front Mol Neurosci. 2017; 10: 234 Crossref PubMed Scopus (35) Google Scholar ). These elevated levels have been linked to deficits in various protein degradation pathways, one of which may involve the autophagy system. Importantly, autophagy is induced by learning and is required for long-term memory formation, which highlights it as a potential player in neurological impairments in AS. SEE CORRESPONDING ARTICLE ON PAGE 68 SEE CORRESPONDING ARTICLE ON PAGE 68 Excessive Protein Accumulation and Impaired Autophagy in the Hippocampus of Angelman Syndrome Modeled in MiceBiological PsychiatryVol. 94Issue 1PreviewAngelman syndrome (AS), a neurodevelopmental disorder caused by abnormalities of the 15q11.2-q13.1 chromosome region, is characterized by impairment of cognitive and motor functions, sleep problems, and seizures. How the genetic defects of AS produce these neurological symptoms is unclear. Mice modeling AS (AS mice) accumulate activity-regulated cytoskeleton-associated protein (ARC/ARG3.1), a neuronal immediate early gene (IEG) critical for synaptic plasticity. This accumulation suggests an altered protein metabolism. Full-Text PDF

Diagnostic value of whole exome sequencing for patients with intellectual disability or global developmental delay

To assess the diagnostic value of whole exome sequencing (WES) for patients with intellectual disability (ID) or global developmental delay (GDD). 134 individuals with ID or GDD who presented at Chenzhou First People's Hospital between May 2018 and December 2021 were selected as the study subjects. WES was carried out on peripheral blood samples of the patients and their parents, and candidate variants were verified by Sanger sequencing, copy number variation sequencing (CNV-seq) and co-segregation analysis. The pathogenicity of the variants was predicted based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). A total of 46 pathogenic single nucleotide variants (SNVs) and small insertion/deletion (InDel) variants, 11 pathogenic genomic copy number variants (CNVs), and 1 uniparental diploidy (UPD) were detected, which yielded an overall detection rate of 43.28% (58/134). The 46 pathogenic SNV/InDel have involved 62 mutation sites in 40 genes, among which MECP2 was the most frequent (n = 4). The 11 pathogenic CNVs have included 10 deletions and 1 duplication, which have ranged from 0.76 to 15.02 Mb. A loss of heterozygosity (LOH) region of approximately 15.62 Mb was detected in 15q11.2q12 region in a patient, which was validated as paternal UPD based on the result of trio-WES. The patient was ultimately diagnosed as Angelman syndrome. WES can detect not only SNV/InDel, but also CNV and LOH. By integrating family data, WES can accurately determine the origin of the variants and provide a useful tool for uncovering the genetic etiology of patients with ID or GDD.

Emergency service perspective of families with children who have neurodevelopmental diseases

Introduction: It is known that children with neurodevelopmental diseases have frequent traumas like falling and apply to emergency department which significantly affects patient and family. Our aim is to examine the families' view and the problems encountered in emergency services by examining their answers to questionnaire.
 Method: This study was designed retrospectively. Patients registered in Department of Autism, Mental Special Needs and Rare Diseases as families with children who have neurodevelopmental diseases included in the study. 324 families’ survey with 12 open-ended questions evaluated in terms of distribution and frequencies with descriptive statistical methods.
 Results: By analyzing the data obtained the findings of the research were gathered under 12 main themes and 80 sub-themes. 313 (89.9%) were diagnosed with Down Syndrome, 9 (2.5%) with Angelman Syndrome, 7 (2.02%) with intellectual disability, and 5 (1.4%) with Autism. 34.2% of the children were 0-3 years old, 28.7% were 3-6 years old, 20.9% were 6-10 years old. Emergency services were used in "all cases where urgent intervention is required" (70%), and in cases where “an outpatient appointment couldn’t made" (10.8%)
 Conclusion: It would be beneficial to examine children with neurodevelopmental diseases in an understanding and patient manner, using a plain and understandable language, in a quiet environment in emergency room. To solve these patient’s problems, awareness training of healthcare professionals, having separate examination and observation room, ensuring accessibility and arranging the room with necessary medical supplies and equipment should be made.

Anesthetic considerations for vagal nerve stimulator implantation in children with Angelman syndrome.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

An Optimal Stacked ResNet-BiLSTM-Based Accurate Detection and Classification of Genetic Disorders.

Gene is located inside the nuclease and the genetic data is contained in deoxyribonucleic acid (DNA). A person's gene count ranges from 20,000 to 30,000. Even a minor alteration to the DNA sequence can be harmful if it affects the cell's fundamental functions. As a result, the gene begins to act abnormally. The sorts of genetic abnormalities brought on by mutation include chromosomal disorders, complex disorders, and single-gene disorders. Therefore, a detailed diagnosis method is required. Thus, we proposed an Elephant Herd Optimization-Whale Optimization Algorithm (EHO-WOA) optimized Stacked ResNet-Bidirectional Long Term Short Memory (ResNet-BiLSTM) model for detecting genetic disorders. Here, a hybrid EHO-WOA algorithm is presented to assess the Stacked ResNet-BiLSTM architecture's fitness. The ResNet-BiLSTM design uses the genotype and gene expression phenotype as input data. Furthermore, the proposed method identifies rare genetic disorders such as Angelman Syndrome, Rett Syndrome, and Prader-Willi Syndrome. It demonstrates the effectiveness of the developed model with greater accuracy, recall, specificity, precision, and f1-score. Thus, a wide range of DNA deficiencies including Prader-Willi syndrome, Marfan syndrome, Early Onset Morbid Obesity, Rett syndrome, and Angelman syndrome are predicted accurately.

Exploring Communication Ability in Individuals With Angelman Syndrome: Findings From Qualitative Interviews With Caregivers.

Communication deficits have a substantial impact on quality of life for individuals with Angelman syndrome (AS) and their families, but limited qualitative work exists to support the necessary content of measures aiming to assess communication for these individuals. Following best practices for concept elicitation studies, we conducted individual qualitative interviews with caregivers and clinicians to elicit meaningful aspects of communication for individuals with AS. Caregivers were able to discuss their child's specific communication behaviors within a large number of expressive, receptive, and pragmatic functions via numerous symbolic and non-symbolic modalities. These results aligned well with published literature on communication in AS and will be used to inform the design of a novel caregiver-reported measure. Future studies on communication in individuals with AS should focus on gathering quantitative data from large samples of diverse caregivers, which would allow for estimations of the frequency of specific behaviors across the population.

Validation of the Observer-Reported Communication Ability (ORCA) Measure for Individuals With Angelman Syndrome.

There is a critical need for high-quality clinical outcome assessments to capture the important aspects of communication ability of individuals with Angelman syndrome (AS). To center the perspective of caregivers, our team developed the novel Observer-Reported Communication Ability (ORCA) measure using best practice guidelines, with the goal of developing a measure that could be administered to caregivers directly without the need for a certified administrator for use in clinical trials. To refine the draft measure, we conducted two rounds of cognitive interviews with 24 caregivers and a quantitative study including 249 caregivers. The results from both studies support the overall content validity, construct validity, and the reliability of the ORCA measure for individuals with AS > 2 years old for use in research contexts. Future work should explore the responsiveness of ORCA measures to changes over time in a diverse sample.

Fragile-X-associated Tremor/Ataxia Syndrome in a Woman with Full Mutation: A Case Report (P5-11.009)

<h3>Objective:</h3> To describe the first case of FXTAS in a full mutation woman without Fragile X syndrome. <h3>Background:</h3> Fragile-X-associated tremor/ataxia syndrome (FXTAS) is caused by expanded trinucleotide (CGG) repeats between 55–199 (premutation) in the <i>Fragile X Mental Retardation 1 (FMR1) gene</i>. Core clinical features of FXTAS include cerebellar ataxia, intention tremor and Parkinsonism. In contrast, a full mutation of CGG repeats&gt;200 repeats with methylation of the gene leads to fragile X syndrome, which is characterized by early intellectual disability, autistic features, and seizures. <i>FMR1</i> premutation carrier women presenting as FXTAS have been reported. This is the first report of a woman with a full mutation presenting with FXTAS. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 65-year-old woman presented with problems with dexterity and shuffling gait. The patient also complained of urinary urgency, constipation, anxiety, depression, and mild cognitive complaints. The patient’s son was diagnosed with fragile X syndrome at 14 months. Neurological exam of the patient showed parkinsonism, action tremor and limb ataxia. MRI brain demonstrated chronic ischemic small vessel disease and mildly reduced brain volume. <i>FMR1 CGG</i> repeat sizes were 20 and &gt;200. The 20 repeat allele was seen on the active X chromosome (representing non-random X-inactivation), while the &gt;200 repeat allele was fully methylated on Southern blot. Testing for Parkinson’s disease-associated genes were negative. <h3>Conclusions:</h3> This is the first report of a woman with a <i>FMR1</i> full mutation presenting with signs and symptoms of FXTAS. Several cases of FXTAS have been reported in <i>FMR1</i> full mutation men with fragile X syndrome due to mosaicism of repeat sizes and the presence of a premutation allele. Full mutation adults with complete methylation have not been reported to have FXTAS. The clinical presentation of this case might be due to size or methylation mosaicism in brain. Alternatively, one could also consider a different disease mimicking FXTAS. <b>Disclosure:</b> Dr. Kazanci has nothing to disclose. The institution of Dr. Berry-Kravis has received research support from NIH. The institution of Dr. Berry-Kravis has received research support from Ovid. The institution of Dr. Berry-Kravis has received research support from Zynerba. The institution of Dr. Berry-Kravis has received research support from Roche. The institution of Dr. Berry-Kravis has received research support from CDC. The institution of Dr. Berry-Kravis has received research support from FRAXA Research Foundation. The institution of Dr. Berry-Kravis has received research support from GeneTx. The institution of Dr. Berry-Kravis has received research support from Angelman Syndrome Foundation. The institution of Dr. Berry-Kravis has received research support from Acadia. The institution of Dr. Berry-Kravis has received research support from GW. The institution of Dr. Berry-Kravis has received research support from Anavex. The institution of Dr. Berry-Kravis has received research support from Rett Syndrome Research Trust. The institution of Dr. Berry-Kravis has received research support from Ultragenyx. The institution of Dr. Berry-Kravis has received research support from Mallinckrodt. The institution of Dr. Berry-Kravis has received research support from Together Strong Foundation. The institution of Dr. Berry-Kravis has received research support from Orphazyme. The institution of Dr. Berry-Kravis has received research support from Ionis. The institution of Dr. Berry-Kravis has received research support from Taysha. The institution of Dr. Berry-Kravis has received research support from Erydel. The institution of Dr. Berry-Kravis has received research support from Tetra. The institution of Dr. Berry-Kravis has received research support from Neuren. The institution of Dr. Berry-Kravis has received research support from FRAXA Research Foundation. Dr. Hall has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier - Parkinsonism and Related Disorders. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Annals of Neurology. The institution of Dr. Hall has received research support from Parkinson’s Foundation. The institution of Dr. Hall has received research support from CHDI. The institution of Dr. Hall has received research support from Biohaven. The institution of Dr. Hall has received research support from Neurocrine. The institution of Dr. Hall has received research support from Uniqure. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as a Study section with NIH.

Trofinetide for the treatment of Rett syndrome: an open-label study in girls 2 to 4 years of age (P13-9.005)

Trofinetide for the treatment of Rett syndrome: an open-label study in girls 2 to 4 years of age (P13-9.005)

Treatment with trofinetide shows benefit compared to placebo for the ability to communicate in individuals with Rett syndrome: a secondary analysis of the LAVENDER study (P13-9.006)

Treatment with trofinetide shows benefit compared to placebo for the ability to communicate in individuals with Rett syndrome: a secondary analysis of the LAVENDER study (P13-9.006)

Imbalanced expression of cation-chloride cotransporters as a potential therapeutic target in an Angelman syndrome mouse model

Angelman syndrome is a neurodevelopmental disorder caused by loss of function of the maternally expressed UBE3A gene. Treatments for the main manifestations, including cognitive dysfunction or epilepsy, are still under development. Recently, the Cl− importer Na+-K+-Cl− cotransporter 1 (NKCC1) and the Cl− exporter K+-Cl− cotransporter 2 (KCC2) have garnered attention as therapeutic targets for many neurological disorders. Dysregulation of neuronal intracellular Cl− concentration ([Cl−]i) is generally regarded as one of the mechanisms underlying neuronal dysfunction caused by imbalanced expression of these cation-chloride cotransporters (CCCs). Here, we analyzed the regulation of [Cl−]i and the effects of bumetanide, an NKCC1 inhibitor, in Angelman syndrome models (Ube3am−/p+ mice). We observed increased NKCC1 expression and decreased KCC2 expression in the hippocampi of Ube3am−/p+ mice. The average [Cl−]i of CA1 pyramidal neurons was not significantly different but demonstrated greater variance in Ube3am−/p+ mice. Tonic GABAA receptor-mediated Cl− conductance was reduced, which may have contributed to maintaining the normal average [Cl−]i. Bumetanide administration restores cognitive dysfunction in Ube3am−/p+ mice. Seizure susceptibility was also reduced regardless of the genotype. These results suggest that an imbalanced expression of CCCs is involved in the pathophysiological mechanism of Ube3am−/p+ mice, although the average [Cl−]i is not altered. The blockage of NKCC1 may be a potential therapeutic strategy for patients with Angelman syndrome.

Health-related quality of life and medication use among individuals with Angelman syndrome.

The primary goal of this analysis is to describe the health-related quality of life (HRQoL), medical history, and medication use among adolescents and adults individuals with Angelman syndrome (AS). The analysis uses baseline data collected during the STARS study, a double-blind placebo controlled trial of gaboxadol (OV101) in adolescents and adults with AS. The HRQoL was estimated using EuroQoL 5-Dimension 5-Level (EQ-5D) health questionnaire proxy 1 version, which was completed by the caregivers. EQ-5D consists of two parts, a 5-dimension descriptive and a visual analogue scale (VAS) component. The utility score derived from EQ-5D ranges from 0 to 1 (perfect health) and VAS ranges from 0 to 100 (perfect health). 87 individuals with AS were included in the present analysis. The mean utility score was 0.44 ± 0.20 and VAS score was 84 ± 1.5. The EQ-5D data indicated that the self-care, mobility and daily activities were most impacted. All adolescents (100%) and most adults (93%) had at least moderate problems with self-care activities, such as washing or dressing themselves. More than half (55%) of the adolescents and adults had at least moderate issues with mobility and usual activities. Approximately, 30% of adolescents and adults had moderate to extreme problems with anxiety/depression. High baseline concomitant use of medications was observed across both age groups with an average of 5 medications being used per person. This study highlights the impact of AS on HRQoL and medication utilization among adolescents and adults individuals with AS.

Quantitative measures of motor development in Angelman syndrome.

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 towardthis maladaptive gait pattern over developmentinpwASages4-11. 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.

A review on Angelman syndrome

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Elevated ROS levels during the early development of Angelman syndrome alter the apoptotic capacity of the developing neural precursor cells

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder caused by the maternally inherited loss of function of the UBE3A gene. AS is characterized by a developmental delay, lack of speech, motor dysfunction, epilepsy, autistic features, happy demeanor, and intellectual disability. While the cellular roles of UBE3A are not fully understood, studies suggest that the lack of UBE3A function is associated with elevated levels of reactive oxygen species (ROS). Despite the accumulating evidence emphasizing the importance of ROS during early brain development and its involvement in different neurodevelopmental disorders, up to date, the levels of ROS in AS neural precursor cells (NPCs) and the consequences on AS embryonic neural development have not been elucidated. In this study we show multifaceted mitochondrial aberration in AS brain-derived embryonic NPCs, which exhibit elevated mitochondrial membrane potential (ΔΨm), lower levels of endogenous reduced glutathione, excessive mitochondrial ROS (mROS) levels, and increased apoptosis compared to wild-type (WT) littermates. In addition, we report that glutathione replenishment by glutathione-reduced ethyl ester (GSH-EE) corrects the excessive mROS levels and attenuates the enhanced apoptosis in AS NPCs. Studying the glutathione redox imbalance and mitochondrial abnormalities in embryonic AS NPCs provides an essential insight into the involvement of UBE3A in early neural development, information that can serve as a powerful avenue towards a broader view of AS pathogenesis. Moreover, since mitochondrial dysfunction and elevated ROS levels were associated with other neurodevelopmental disorders, the findings herein suggest some potential shared underlying mechanisms for these disorders as well.

An ASO therapy for Angelman syndrome that targets an evolutionarily conserved region at the start of the UBE3A-AS transcript.

Angelman syndrome is a devastating neurogenetic disorder for which there is currently no effective treatment. It is caused by mutations or epimutations affecting the expression or function of the maternally inherited allele of the ubiquitin-protein ligase E3A (UBE3A) gene. The paternal UBE3A allele is imprinted in neurons of the central nervous system (CNS) by the UBE3A antisense (UBE3A-AS) transcript, which represents the distal end of the small nucleolar host gene 14 (SNHG14) transcription unit. Reactivating the expression of the paternal UBE3A allele in the CNS has long been pursued as a therapeutic option for Angelman syndrome. Here, we described the development of an antisense oligonucleotide (ASO) therapy for Angelman syndrome that targets an evolutionarily conserved region demarcating the start of the UBE3A-AS transcript. We designed and chemically optimized gapmer ASOs targeting specific sequences at the start of the human UBE3A-AS transcript. We showed that ASOs targeting this region precisely and efficiently repress the transcription of UBE3A-AS, reactivating the expression of the paternal UBE3A allele in neurotypical and Angelman syndrome induced pluripotent stem cell-derived neurons. We further showed that human-targeted ASOs administered to the CNS of cynomolgus macaques by lumbar intrathecal injection repress UBE3A-AS and reactivate the expression of the paternal UBE3A allele throughout the CNS. These findings support the advancement of this investigational molecular therapy for Angelman syndrome into clinical development (ClinicalTrials.gov, NCT04259281).

Identification of novel variations of oculocutaneous albinism type 2 with Prader-Willi syndrome/Angelman syndrome in two Chinese families.

Objective: Oculocutaneous albinism (OCA) is an autosomal recessive disorder caused by a variety of genomic variations. Our aim is to identify the molecular basis of OCA in two families and lay the foundation for prenatal diagnosis. Methods: Four types of OCA-causing mutations in the TYR, p, TYRP1, or SLC45A2 genes were screened. Linkage analysis was performed because the mutations found in the p gene violated the laws of classical Mendelian heredity. Primer-walking sequencing combined with microsatellite and single-nucleotide polymorphism analysis was used to ascertain deletion ranges. Bioinformatics methods were used to assess the pathogenicity of the new mutations. Results: Proband 1 was diagnosed as OCA2 with Prader-Willi syndrome (PWS) due to a novel atypical paternal deletion (chromosome 15: 22330347-26089649) and a pathogenic mutation, c.1327G>A (Val443Ile), in the p gene of the maternal chromosome. The prenatal diagnosis results for family 1 indicated the fetus was a heterozygous carrier (c.1327G>A in the p gene) with a normal phenotype. Proband 2 was diagnosed as OCA2 with Angelman syndrome (AS) due to a typical maternal deletion of chromosome 15q11-q13 and a novel mutation, c.1514T>C (Phe505Ser), in the p gene of the paternal chromosome. This novel mutation c.1514T>C (Phe505Ser) in the p gene was predicted as a pathogenic mutation. Conclusion: Our study has shown clear genotype-phenotype correlations in patients affected by distinct deletions of the PWS or AS region and missense mutations in the p gene. Our results have enriched the mutation spectrum of albinism diseases and provided insights for more accurate diagnosis and genetic counseling.

Linoleic acid improves PIEZO2 dysfunction in a mouse model of Angelman Syndrome

Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability and atypical behaviors. AS results from loss of expression of the E3 ubiquitin-protein ligase UBE3A from the maternal allele in neurons. Individuals with AS display impaired coordination, poor balance, and gait ataxia. PIEZO2 is a mechanosensitive ion channel essential for coordination and balance. Here, we report that PIEZO2 activity is reduced in Ube3a deficient male and female mouse sensory neurons, a human Merkel cell carcinoma cell line and female human iPSC-derived sensory neurons with UBE3A knock-down, and de-identified stem cell-derived neurons from individuals with AS. We find that loss of UBE3A decreases actin filaments and reduces PIEZO2 expression and function. A linoleic acid (LA)-enriched diet increases PIEZO2 activity, mechano-excitability, and improves gait in male AS mice. Finally, LA supplementation increases PIEZO2 function in stem cell-derived neurons from individuals with AS. We propose a mechanism whereby loss of UBE3A expression reduces PIEZO2 function and identified a fatty acid that enhances channel activity and ameliorates AS-associated mechano-sensory deficits.

Angelman syndrome in two siblings: clinical case

Background. Angelman syndrome (AS) is rare genetic disease characterized by severe mental retardation, gross developmental speech delay, facial dysmorphia, disorders of motor activity, behavior and sleep, epileptic seizures manifestation. Pathology refers to diseases of genomic imprinting. There are four possible mechanisms of pathology development in Angelman syndrome: 15q11.2-q13 deletion on the chromosome 15 of maternal origin, mutation of the ubiquitin ligase (UBE3A) gene at the 15q11.2 locus on the chromosome 15 of maternal origin, uniparental disomy of the 15q11.2-q13 region of paternal origin, imprinting center defect.Clinical case description. Clinical picture of Angelman syndrome in two twin sibs (boy E., girl V.) observed in Children’s City Clinical Hospital № 1 in Nizhny Novgorod is presented. Children from consecutive pregnancy with dichorionic-diamniotic twins; preterm birth at 30 weeks. There was burdened obstetric-biological and perinatal history due to the threatened miscarriage during this pregnancy and due to asphyxia of both children during delivery. The disease has classical course in both patients: static functions development delay, gross developmental speech and intellectual delay, behavioral and motor disorders (stereotypy, tremor, ataxia, episodes of unmotivated laughter, sleep disorders), presence of typical facial dysmorphia. This diagnosis was confirmed by the molecular genetic study (boy — mutation in exon 7 of the UBE3A gene, girl — mutations in exons 6 and 7 of the UBE3A gene). Features of epileptic seizure therapy in both patients are presented.Conclusion. The presented clinical case demonstrates typical clinical picture of AS in two sibs confirmed by molecular genetic study. The therapy of this syndrome is very complicated. The described patients require constant anticonvulsant therapy, observation of neurologist, psychotherapist, working with speech pathologist. Complete correction of this syndrome is impossible.

Social attention and social-emotional modulation of attention in Angelman syndrome: an eye-tracking study

Individuals with Angelman syndrome (AS) present with severe intellectual disability alongside a social phenotype characterised by social communication difficulties and an increased drive for social engagement. As the social phenotype in this condition is poorly understood, we examined patterns of social attention and social modulation of attention in AS. Twenty-four individuals with AS and twenty-one young children with similar mental age were shown videos featuring unfamiliar actors who performed simple actions across two conditions: a playful condition, in which the actor showed positive facial emotions, and a neutral condition, in which the actor showed a neutral facial expression. During the passive observation of the videos, participants’ proportion of time spent watching the two areas of interest (faces and actions) was examined using eye-tracking technology. We found that the playful condition elicited increased proportion of fixations duration to the actor’s face compared to the neutral condition similarly across groups. Additionally, the proportion of fixations duration to the action area was similar across groups in the two conditions. However, children with AS looked towards the actor’s face for a shorter duration compared to the comparison group across conditions. This pattern of similarities and differences provides novel insight on the complex social phenotype of children with AS.