scholarly journals Anxiety in Angelman Syndrome

2022 ◽  
Vol 127 (1) ◽  
pp. 1-10
Author(s):  
Stacey C. Grebe ◽  
Danica L. Limon ◽  
Morgan M. McNeel ◽  
Andrew Guzick ◽  
Sarika U. Peters ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Chromosome 15 ◽  
Limited Information ◽  
Measurement Instruments ◽  
Natural History Study ◽  
Developmental Behavior ◽  
Ube3a Gene ◽  
Specific Symptoms

Abstract Angelman Syndrome (AS) is a neurodevelopmental disorder most commonly caused by the impaired expression of the maternal UBE3A gene on chromosome 15. Though anxiety has been identified as a frequently present characteristic in AS, there are limited studies examining anxiety in this population. Studies of anxiety in other neurodevelopmental disorders have found disorder specific symptoms of anxiety and age specific displays of anxiety symptoms. However, there is a consistent challenge in identifying anxiety in people with neurodevelopmental disorders given the lack of measurement instruments specifically designed for this population. Given the limited information about AS and anxiety, the aims of the current project were to (a) examine symptoms of anxiety in children with AS and (b) determine the correlates of anxiety in children with AS. Participants included 42 adult caregivers of youth with AS in the AS Natural History study who completed the Developmental Behavior Checklist (DBC). The results found that 26% of the sample demonstrated elevated symptoms of anxiety and established a relationship between elevated anxiety in youth with AS and higher levels of irritability, hyperactivity, self-absorbed behaviors, and disruptive/antisocial behaviors. Findings from this research provide a foundation for tailoring evidence-based assessments and treatments for youth with AS and anxiety.

scholarly journals Angelman Syndrome: An Autism Spectrum Disorder

2018 ◽  
Vol 6 (2) ◽  
pp. 56-60
Author(s):  
Andrew J. Kennedy ◽  
Jeffrey O. Henderson
Keyword(s):  
Angelman Syndrome ◽  
Motor Development ◽  
Neurodevelopmental Disorders ◽  
Muscle Tension ◽  
Autism Spectrum ◽  
Speech Impairment ◽  
Social Lives ◽  
Genetic Abnormalities ◽  
Ube3a Gene ◽  
Genetic Mechanisms

Neurodevelopmental disorders limit the mental, physical, and social lives of affected individuals and their families. These disorders are often related to genetic abnormalities having a distinct chromosomal location. The abnormalities can cause incorrect proteins to be formed or biochemical pathways to be blocked, predominately affecting brain development, but also having pleiotropic effects. Research into defining and correcting these genetic abnormalities is important to help distinguish between unique neurodevelopmental disorders so that proper clinical interventions are available for affected individuals. In the following review, Angelman syndrome, which results from UBE3A gene function being lost at maternal chromosome  15q11.2-q13, will be discussed. Angelman patients suffer from the defining characteristics of speech impairment, uncontrolled laughing and smiling, motor development issues, muscle tension, and possible ataxia. The genetic mechanisms of the disorder as well as possible therapies will be discussed, with future areas of research into genetic therapies to treat Angelman syndrome also put forth. Research into Angelman syndrome can provide an avenue for a clearer understanding of other neurodevelopmental disorders.

scholarly journals Loss of nuclear UBE3A activity is the predominant cause of Angelman syndrome in individuals carrying UBE3A missense mutations

2021 ◽  
Author(s):  
Stijn N V Bossuyt ◽  
A Mattijs Punt ◽  
Ilona J de Graaf ◽  
Janny van den Burg ◽  
Mark G Williams ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Angelman Syndrome ◽  
Neurodevelopmental Disorder ◽  
Critical Role ◽  
Rapid Assessment ◽  
Missense Mutations ◽  
Catalytic Potential ◽  
Ubiquitin Ligase Activity ◽  
Ube3a Gene

Abstract Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by deletion (~75%) or mutation (~10%) of the UBE3A gene, which encodes a HECT type E3 ubiquitin protein ligase. Although the critical substrates of UBE3A are unknown, previous studies have suggested a critical role of nuclear UBE3A in AS pathophysiology. Here we investigated to what extent UBE3A missense mutations disrupt UBE3A subcellular localization as well as catalytic activity, stability and protein folding. Our functional screen of 31 UBE3A missense mutants revealed that UBE3A mislocalization is the predominant cause of UBE3A dysfunction, accounting for 55% of the UBE3A mutations tested. The second major cause (29%) is a loss of E3-ubiquitin ligase activity, as assessed in an E. coli in vivo ubiquitination assay. Mutations affecting catalytic activity are found not only in the catalytic HECT domain, but also in the N-terminal half of UBE3A, suggesting an important contribution of this N-terminal region to its catalytic potential. Together, our results show that loss of nuclear UBE3A E3 ligase activity is the predominant cause of UBE3A-linked Angelman syndrome. Moreover, our functional analysis screen allows rapid assessment of the pathogenicity of novel UBE3A missense variants which will be of particular importance when treatments for AS become available.

Angelman Syndrome-Affected Individual with a Numerically Normal Karyotype and Isodisomic Paternal Uniparental Disomy of Chromosome 15 due to Maternal Robertsonian Translocation (14;15) by Monosomy Rescue

2018 ◽  
Vol 156 (1) ◽  
pp. 9-13 ◽  
Author(s):  
Nuria C. Bramswig ◽  
Karin Buiting ◽  
Natalie Bechtel ◽  
Bernhard Horsthemke ◽  
Kevin Rostasy ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
Robertsonian Translocation ◽  
Chromosome Region ◽  
Neurodevelopmental Disorder ◽  
Uniparental Disomy ◽  
Normal Karyotype ◽  
Early Embryo ◽  
Affected Individual ◽  
Chromosome 15 ◽  
Paternal Uniparental Disomy

Angelman syndrome (AS) is a neurodevelopmental disorder caused by deletion of the maternally inherited 15q11q13 region, paternal uniparental disomy 15 [upd(15)pat], an imprinting defect of the maternal chromosome region 15q11q13, or a pathogenic mutation of the maternal UBE3A allele. Predisposing factors for upd(15)pat, such as nonhomologous robertsonian translocation involving chromosome 15, have been discussed, but no evidence for this predisposition has been published. In the present study, chromosomal analysis was performed in a child with AS, both parents, and the maternal grandparents. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was employed on DNA of the index individual, and microsatellite analysis was carried out on DNA of the index individual and his parents. The cytogenetic analysis showed that the mother and maternal grandfather are carriers of a rob(14;15). The index individual has a numerically normal karyotype, but MS-MLPA and microsatellite analyses confirmed the clinical diagnosis of AS and revealed a pattern highly suggestive of isodisomic upd(15)pat. This is the first report of an AS-affected individual with isodisomic upd(15)pat and a numerically normal karyotype that most likely results from a rob(14;15)-associated meiotic error in the maternal germline followed by monosomy 15 rescue in the early embryo.

796 Quantitative EEG Analysis in Angelman Syndrome

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A310-A310
Author(s):  
Nishitha Hosamane ◽  
Yuval Levin ◽  
Taylor McNair ◽  
Michael Sidorov
Keyword(s):  
Clinical Trials ◽  
Angelman Syndrome ◽  
Neurodevelopmental Disorder ◽  
Quantitative Eeg ◽  
Great Promise ◽  
Sleep Spindles ◽  
Chromosome 15 ◽  
Eeg Analysis ◽  
Potential Biomarker ◽  
Quantitative Eeg Analysis

Abstract Introduction Angelman syndrome (AS) is a neurodevelopmental disorder resulting from decreased expression of the maternal copy of the imprinted UBE3A gene on chromosome 15. This disorder is characterized by intellectual disability, impaired speech and motor skills, and sleep abnormalities but currently lacks any treatment. However, mouse models have shown that un-silencing the dormant paternal copy of UBE3A has been an effective mechanism to restore the functionality of the UBE3A protein, thus clinical trials using this approach are on the near horizon. Developing biomarkers is essential for assessing responses to treatment when clinical trials begin, and quantitative EEG analysis has shown great promise as a biomarker for AS. Methods Here, we sought to define EEG biomarkers directly linked to sleep impairments seen in up to 90% of individuals with AS (Trickett). We analyzed nine overnight sleep studies from patients with AS with age and sex matched Down syndrome and neurotypical controls. We specifically examined low-frequency delta rhythms and sleep spindles during NREM sleep. Results We confirmed that low- delta rhythms are increased during overnight sleep in AS, and that this biomarker appears more reliable than possible changes in sleep spindles. Conclusion Our results suggest that quantitative measurement of delta rhythms during sleep can be used as a potential biomarker for treatments in Angelman syndrome clinical trials. Support (if any):

scholarly journals Molecular-Genetic Diagnostics of Angelman Syndrome – The Bulgarian Experience

2020 ◽  
Vol 47 (1) ◽  
pp. 9-16
Author(s):  
B. Georgieva ◽  
S. Atemin ◽  
A. Todorova ◽  
T. Todorov ◽  
A. Miteva ◽  
...  
Keyword(s):  
Clinical Diagnosis ◽  
Angelman Syndrome ◽  
Molecular Mechanisms ◽  
Neurodevelopmental Disorder ◽  
Molecular Genetic ◽  
Regulatory Region ◽  
Uniparental Disomy ◽  
Pcr Multiplex ◽  
Ube3a Gene ◽  
Mechanisms Of Mutagenesis

AbstractObjective: The aim of the study was to determine the molecular mechanisms of mutagenesis in Bulgarian patients with Angelman syndrome (AS). AS is a severe neurodevelopmental disorder caused by loss of expression in brain of the maternally inherited UBE3A gene as a result of various 15q11.2-q13 alterations.Material and Methods: In total 24 patients (11 boys, 13 girls) from 22 unrelated families with suspected clinical diagnosis AS were analysed. We used methylation specific PCR, multiplex ligation-dependent probe amplification, methylation sensitive MLPA, and direct sequencing of the UBE3A gene.Results: In 9 families (41%) pathogenic mutations were detected, which confirmed the clinical diagnosis on а molecular-genetic level. In 4 (44%) of these families we found 15q11-q13 region deletion with breakpoints BP1-BP3 or BP2-BP3. In 1 (11%) of the families we found imprinting defect: deletion of the AS-SRO regulatory region (part of the PWS-AS imprinting center). In 1 (11%) of the families we detected a rare finding – paternal uniparental disomy of chromosome 15. In 3 (33%) of the families diff erent point mutations in the UBE3A gene were detected: two novel missence mutations c.488T > C; p.Leu163Ser and c.1832A > T; p.Gln611Leu, and one known frameshift mutation c.2576_2579delAAGA; p.Lys859Argfs*4.Conclusion: The obtained results helped us to develop a systematic diagnostic algorithm in order to provide proper diagnosis for the patients with AS. Combining excellent knowledge of the molecular mechanisms of mutagenesis and proper molecular-genetic testing approaches is a cornerstone in the management of AS patients, ensuring AS families would receive both adequate genetic counseling and prophylaxis of the disease in the future.

scholarly journals Aberrant aggressive behavior in a mouse model of Angelman syndrome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lilach Simchi ◽  
Hanoch Kaphzan
Keyword(s):  
Social Behavior ◽  
Mouse Model ◽  
Aggressive Behavior ◽  
Social Interactions ◽  
Angelman Syndrome ◽  
Case Reports ◽  
Neurodevelopmental Disorder ◽  
Therapeutic Interventions ◽  
Affiliative Behavior ◽  
Severe Difficulty

AbstractAngelman syndrome (AS) is a genetic neurodevelopmental disorder due to the absence of the E3-ligase protein, UBE3A. Inappropriate social interactions, usually hyper-sociability, is a part of that syndrome. In addition, clinical surveys and case reports describe aggressive behavior in AS individuals as a severe difficulty for caretakers. A mouse model for AS recapitulates most of the human AS phenotypes. However, very few studies utilized this mouse model for investigating affiliative social behavior, and not even a single study examined aggressive behavior. Hence, the aim of the herein study was to examine affiliative and aggressive social behavior. For that, we utilized a battery of behavioral paradigms, and performed detailed analyses of these behaviors. AS mice exhibited a unique characteristic of reduced habituation towards a social stimulus in comparison to their wild-type (WT) littermates. However, overall there were no additional marked differences in affiliative social behavior. In contrast to the mild changes in affiliative behavior, there was a striking enhanced aggression in the AS mice compared to their WT littermates. The herein findings emphasize the use of AS mouse model in characterizing and measuring inappropriate aggressive behavior, and suggests these as tools for investigating therapeutic interventions aimed at attenuating aggressive behavior.

scholarly journals LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models

2021 ◽  
Vol 7 (11) ◽  
pp. eaba1187
Author(s):  
Rina Baba ◽  
Satoru Matsuda ◽  
Yuuichi Arakawa ◽  
Ryuji Yamada ◽  
Noriko Suzuki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Enzyme Activity ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Specific Inhibitor ◽  
Autism Spectrum ◽  
Poly I:C ◽  
Control Of Gene Expression ◽  
Epigenetic Machinery ◽  
The Brain

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

scholarly journals Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joseph J. Rossi ◽  
Jill A. Rosenfeld ◽  
Katie M. Chan ◽  
Haley Streff ◽  
Victoria Nankivell ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Protein Function ◽  
Transcriptional Activity ◽  
Neurodevelopmental Disorder ◽  
Complete Loss ◽  
Loss Of Function ◽  
Targeted Disruption ◽  
Clinical Exome Sequencing ◽  
Partner Protein ◽  
The Brain

AbstractAberrations in the excitatory/inhibitory balance within the brain have been associated with both intellectual disability (ID) and schizophrenia (SZ). The bHLH-PAS transcription factors NPAS3 and NPAS4 have been implicated in controlling the excitatory/inhibitory balance, and targeted disruption of either gene in mice results in a phenotype resembling ID and SZ. However, there are few human variants in NPAS3 and none in NPAS4 that have been associated with schizophrenia or neurodevelopmental disorders. From a clinical exome sequencing database we identified three NPAS3 variants and four NPAS4 variants that could potentially disrupt protein function in individuals with either developmental delay or ID. The transcriptional activity of the variants when partnered with either ARNT or ARNT2 was assessed by reporter gene activity and it was found that variants which truncated the NPAS3/4 protein resulted in a complete loss of transcriptional activity. The ability of loss-of-function variants to heterodimerise with neuronally enriched partner protein ARNT2 was then determined by co-immunoprecipitation experiments. It was determined that the mechanism for the observed loss of function was the inability of the truncated NPAS3/4 protein to heterodimerise with ARNT2. This further establishes NPAS3 and NPAS4 as candidate neurodevelopmental disorder genes.

scholarly journals Angelman Syndrome and Angelman-like Syndromes Share the Same Calcium-Related Gene Signatures

2021 ◽  
Vol 22 (18) ◽  
pp. 9870
Author(s):  
Julia Panov ◽  
Hanoch Kaphzan
Keyword(s):  
Angelman Syndrome ◽  
Neurodevelopmental Disorders ◽  
Clinical Presentation ◽  
Rna Seq ◽  
Related Gene ◽  
Bioinformatics Analyses ◽  
Gene Signatures ◽  
Signature Genes ◽  
Gene Expression Analyses ◽  
Differential Gene

Angelman-like syndromes are a group of neurodevelopmental disorders that entail clinical presentation similar to Angelman Syndrome (AS). In our previous study, we showed that calcium signaling is disrupted in AS, and we identified calcium-target and calcium-regulating gene signatures that are able to differentiate between AS and their controls in different models. In the herein study, we evaluated these sets of calcium-target and calcium-regulating genes as signatures of AS-like and non-AS-like syndromes. We collected a number of RNA-seq datasets of various AS-like and non-AS-like syndromes and performed Principle Component Analysis (PCA) separately on the two sets of signature genes to visualize the distribution of samples on the PC1–PC2 plane. In addition to the evaluation of calcium signature genes, we performed differential gene expression analyses to identify calcium-related genes dysregulated in each of the studied syndromes. These analyses showed that the calcium-target and calcium-regulating signatures differentiate well between AS-like syndromes and their controls. However, in spite of the fact that many of the non-AS-like syndromes have multiple differentially expressed calcium-related genes, the calcium signatures were not efficient classifiers for non-AS-like neurodevelopmental disorders. These results show that features based on clinical presentation are reflected in signatures derived from bioinformatics analyses and suggest the use of bioinformatics as a tool for classification.

scholarly journals Parental infections disrupt clustered genes encoding related functions required for nervous system development in newborns

2018 ◽  
Author(s):  
Bernard Friedenson
Keyword(s):  
Dna Sequences ◽  
Neurodevelopmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Gene Clusters ◽  
Nervous System Development ◽  
Driver Mutations ◽  
Large Chromosome ◽  
Chromosomal Anomalies ◽  
Chromosome Anomalies ◽  
Human Dna

AbstractThe purpose of this study was to understand the role of infection in the origin of chromosomal anomalies linked to neurodevelopmental disorders. In children with disorders in the development of their nervous systems, chromosome anomalies known to cause these disorders were compared to viruses and bacteria including known teratogens. Results support the explanation that parental infections disrupt elaborate multi-system gene coordination needed for neurodevelopment. Genes essential for neurons, lymphatic drainage, immunity, circulation, angiogenesis, cell barriers, structure, and chromatin activity were all found close together in polyfunctional clusters that were deleted in neurodevelopmental disorders. These deletions account for immune, circulatory, and structural deficits that accompany neurologic deficits. In deleted gene clusters, specific and repetitive human DNA matched infections and passed rigorous artifact tests. In some patients, epigenetic driver mutations were found and may be functionally equivalent to deleting a cluster or changing topologic chromatin interactions because they change access to large chromosome segments. In three families, deleted DNA sequences were associated with intellectual deficits and were not included in any database of genomic variants. These sequences were thousands of bp and unequivocally matched foreign DNAs. Analogous homologies were also found in chromosome anomalies of a recurrent neurodevelopmental disorder. Viral and bacterial DNAs that match repetitive or specific human DNA segments are thus proposed to interfere with highly active break repair during meiosis; sometimes delete polyfunctional clusters, and disable epigenetic drivers. Mis-repaired gametes produce zygotes containing rare chromosome anomalies which cause neurologic disorders and accompanying non-neurologic signs. Neurodevelopmental disorders may be examples of assault on the human genome by foreign DNA with some infections more likely tolerated because they resemble human DNA segments. Further tests of this model await new technology.Graphic Abstract

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