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Journal of Pineal Research Nov 2020In 1965, Dr Harry Angelman reported a neurodevelopmental disorder affecting three unrelated children who had similar symptoms: brachycephaly, mental retardation, ataxia,... (Review)
Review
In 1965, Dr Harry Angelman reported a neurodevelopmental disorder affecting three unrelated children who had similar symptoms: brachycephaly, mental retardation, ataxia, seizures, protruding tongues, and remarkable paroxysms of laughter. Over the past 50 years, the disorder became Angelman's namesake and symptomology was expanded to include hyper-activity, stereotypies, and severe sleep disturbances. The sleep disorders in many Angelman syndrome (AS) patients are broadly characterized by difficulty falling and staying asleep at night. Some of these patients sleep less than 4 hours a night and, in most cases, do not make up this lost sleep during the day-leading to the speculation that AS patients may "need" less sleep. Most AS patients also have severely reduced levels of melatonin, a hormone produced by the pineal gland exclusively at night. This nightly pattern of melatonin production is thought to help synchronize internal circadian rhythms and promote nighttime sleep in humans and other diurnal species. It has been proposed that reduced melatonin levels contribute to the sleep problems in AS patients. Indeed, emerging evidence suggests melatonin replacement therapy can improve sleep in many AS patients. However, AS mice show sleep problems that are arguably similar to those in humans despite being on genetic backgrounds that do not make melatonin. This suggests the hypothesis that the change in nighttime melatonin may be a secondary factor rather than the root cause of the sleeping disorder. The goals of this review article are to revisit the sleep and melatonin findings in both AS patients and animal models of AS and discuss what AS may tell us about the underlying mechanisms of, and interplay between, melatonin and sleep.
Topics: Angelman Syndrome; Animals; Circadian Rhythm; Humans; Melatonin; Pineal Gland; Sleep Wake Disorders
PubMed: 32976638
DOI: 10.1111/jpi.12697 -
International Journal of Molecular... Sep 2021Angelman-like syndromes are a group of neurodevelopmental disorders that entail clinical presentation similar to Angelman Syndrome (AS). In our previous study, we showed...
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.
Topics: Angelman Syndrome; Calcium; Calcium Signaling; Chromosome Deletion; Computational Biology; Gene Expression Regulation; Humans; Principal Component Analysis; RNA-Seq
PubMed: 34576033
DOI: 10.3390/ijms22189870 -
European Journal of Medical Genetics Feb 2023The CpG island flanking the promoter region of SNRPN on chromosome 15q11.2 contains CpG sites that are completely methylated in the maternally derived allele and...
The CpG island flanking the promoter region of SNRPN on chromosome 15q11.2 contains CpG sites that are completely methylated in the maternally derived allele and unmethylated in the paternally derived allele. Both unmethylated and methylated alleles are observed in normal individuals. Only the methylated allele is observed in patients with Prader-Willi syndrome, whereas only the unmethylated allele is observed in those with Angelman syndrome. Hence, detection of aberrant methylation at the differentially methylated region is fundamental to the molecular diagnosis of Prader-Willi syndrome and Angelman syndromes. Traditionally, bisulfite treatment and methylation-sensitive restriction enzyme treatment or methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) have been used. We here developed a long-read sequencing assay that can distinguish methylated and unmethylated CpG sites at 15q11.2 by the difference in current intensity generated from nanopore reads. We successfully diagnosed 4 Prader-Willi syndrome patients and 3 Angelman syndrome patients by targeting differentially methylated regions. Concurrent copy number analysis, homozygosity analysis, and structural variant analysis also allowed us to precisely delineate the underlying pathogenic mechanisms, including gross deletion, uniparental heterodisomy, uniparental isodisomy, or imprinting defect. Furthermore, we showed allele-specific methylation in imprinting-related differentially methylated regions on chromosomes 6, 7, 11, 14, and 20 in a normal individual together with 4 Prader-Willi patients and 3 Angelman syndrome patients. Hence, presently reported method is likely to be applicable to the diagnosis of imprinting disorders other than Prader-Willi syndrome and Angelman syndrome as well.
Topics: Humans; Prader-Willi Syndrome; Angelman Syndrome; DNA Methylation; Nanopores; Uniparental Disomy; Chromosomes, Human, Pair 15; Genomic Imprinting
PubMed: 36587803
DOI: 10.1016/j.ejmg.2022.104690 -
ELife Feb 2023Experiments on mice suggest that an approach called antisense oligonucleotide therapy may be able to treat some symptoms of Angelman syndrome, including problems with...
Experiments on mice suggest that an approach called antisense oligonucleotide therapy may be able to treat some symptoms of Angelman syndrome, including problems with epilepsy and sleep.
Topics: Animals; Mice; Angelman Syndrome; Epilepsy; Sleep; Disease Models, Animal; Ubiquitin-Protein Ligases
PubMed: 36749315
DOI: 10.7554/eLife.86117 -
Autism Research : Official Journal of... Jan 2020Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by mutation or deletion of the maternally inherited UBE3A allele. These pathogenic mutations lead to... (Review)
Review
Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by mutation or deletion of the maternally inherited UBE3A allele. These pathogenic mutations lead to loss of maternal UBE3A expression in neurons. Antisense oligonucleotides and gene therapies are in development, which activate the intact but epigenetically silenced paternal UBE3A allele. Preclinical studies indicate that treating during the prenatal period could greatly reduce the severity of symptoms or prevent AS from developing. Genetic tests can detect the chromosome 15q11-q13 deletion that is the most common cause of AS. New, highly sensitive noninvasive prenatal tests that take advantage of single-cell genome sequencing technologies are expected to enter the clinic in the coming years and make early genetic diagnosis of AS more common. Efforts are needed to identify fetuses and newborns with maternal 15q11-q13 deletions and to phenotype these babies relative to neurotypical controls. Clinical and parent observations suggest AS symptoms are detectable in infants, including reports of problems with feeding and motor function. Quantitative phenotypes in the 0- to 1-year age range will permit a more rapid assessment of efficacy when future treatments are administered prenatally or shortly after birth. Although prenatal therapies are currently not available for AS, prenatal testing combined with prenatal treatment has the potential to revolutionize how clinicians detect and treat babies before they are symptomatic. This pioneering prenatal treatment path for AS will lay the foundation for treating other syndromic neurodevelopmental disorders. Autism Res 2020, 13: 11-17. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Prenatal treatment could benefit expectant parents whose babies test positive for the chromosome microdeletion that causes Angelman syndrome (AS). Prenatal treatment is predicted to have better outcomes than treating after symptoms develop and may even prevent AS altogether. This approach could generally be applied to the treatment of other syndromic neurodevelopmental disorders.
Topics: Angelman Syndrome; Female; Genetic Testing; Genetic Therapy; Humans; Neurodevelopmental Disorders; Pregnancy; Prenatal Diagnosis
PubMed: 31490639
DOI: 10.1002/aur.2203 -
Oncotarget Feb 2017
Topics: Angelman Syndrome; Animals; Autism Spectrum Disorder; Endocytosis; Gene Expression Regulation; Hippocampus; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Protein Domains; Protein Kinase C-alpha; Signal Transduction; TOR Serine-Threonine Kinases; Ubiquitin-Protein Ligases
PubMed: 28179584
DOI: 10.18632/oncotarget.15105 -
Neuroscience Oct 2020The UBE3A gene is part of the chromosome 15q11-q13 region that is frequently deleted or duplicated, leading to several neurodevelopmental disorders (NDD). Angelman... (Review)
Review
The UBE3A gene is part of the chromosome 15q11-q13 region that is frequently deleted or duplicated, leading to several neurodevelopmental disorders (NDD). Angelman syndrome (AS) is caused by the absence of functional maternally derived UBE3A protein, while the paternal UBE3A gene is present but silenced specifically in neurons. Patients with AS present with severe neurodevelopmental delay, with pronounced motor deficits, absence of speech, intellectual disability, epilepsy, and sleep problems. The pathophysiology of AS is still unclear and a treatment is lacking. Animal models of AS recapitulate the genotypic and phenotypic features observed in AS patients, and have been invaluable for understanding the disease process as well as identifying apropriate drug targets. Using these AS mouse models we have learned that loss of UBE3A probably affects many areas of the brain, leading to increased neuronal excitability and a loss of synaptic spines, along with changes in a number of distinct behaviours. Inducible AS mouse models have helped to identify the critical treatment windows for the behavioral and physiological phenotypes. Additionally, AS mouse models indicate an important role for the predominantly nuclear UBE3A isoform in generating the characteristic AS pathology. Last, but not least, the AS mice have been crucial in guiding Ube3a gene reactivation treatments, which present a very promising therapy to treat AS.
Topics: Angelman Syndrome; Animals; Disease Models, Animal; Humans; Male; Mice; Neurons; Phenotype; Ubiquitin-Protein Ligases
PubMed: 32088294
DOI: 10.1016/j.neuroscience.2020.02.017 -
Seizure Jun 1999Angelman syndrome is a neurogenetic condition namely characterized by developmental delay, virtual absence of expressive verbal language, peculiar organization of...
Angelman syndrome is a neurogenetic condition namely characterized by developmental delay, virtual absence of expressive verbal language, peculiar organization of movement, seizures and happy demeanor. This syndrome has been recognized since 1965, but it seems that Walt Disney presented an original depiction of it in his first full-length animated film, including myoclonic jerks and an apparently generalized tonic-clonic seizure.
Topics: Angelman Syndrome; Cartoons as Topic; Child; Epilepsies, Myoclonic; Humans; Language Development Disorders; Medicine in the Arts; Motion Pictures; Sick Role
PubMed: 10452923
DOI: 10.1053/seiz.1999.0289 -
Developmental Medicine and Child... Nov 2019A scoping review was conducted to examine and evaluate empirical data on the communication profile of Angelman syndrome beyond the described dissociation between... (Review)
Review
AIM
A scoping review was conducted to examine and evaluate empirical data on the communication profile of Angelman syndrome beyond the described dissociation between receptive language and speech.
METHOD
Three databases (PsycINFO, Embase, and Web of Science) were searched to retrieve articles investigating communication in Angelman syndrome. Seventeen articles investigating the broader communication profile were found; their methodology was evaluated against quality criteria.
RESULTS
Despite the absence of speech, individuals with Angelman syndrome have a wide repertoire of non-verbal communicative behaviours, mainly characterized by gestures, although advanced forms such as symbolic communication are used by some individuals. The use of communicative forms differs between the genetic aetiologies of Angelman syndrome; individuals with non-deletion aetiologies typically have greater communicative abilities.
INTERPRETATION
The broader communication profile of Angelman syndrome is characterized by diverse and multimodal abilities, including some use of symbolic forms of communication that appears atypical given the absence of speech. This is suggestive of a probable dissociation between speech and other expressive forms of communication, indicating an isolated speech production impairment. This highlights a need in this population for alternative communication and specific input from services tailored to support the nuances of the communication profile of Angelman syndrome.
WHAT THIS PAPER ADDS
Although absent speech is near universal, a diverse profile of other communicative abilities has been reported. Parental reporting has been predominantly used to assess the communication profile of Angelman syndrome. Literature that investigates the specificities and possible dissociations in such a communication profile is limited.
Topics: Angelman Syndrome; Communication; Humans; Nonverbal Communication; Speech
PubMed: 31074506
DOI: 10.1111/dmcn.14257 -
JCI Insight Oct 2021Loss of the maternal UBE3A allele causes Angelman syndrome (AS), a debilitating neurodevelopmental disorder. Here, we devised an AS treatment strategy based on...
Loss of the maternal UBE3A allele causes Angelman syndrome (AS), a debilitating neurodevelopmental disorder. Here, we devised an AS treatment strategy based on reinstating dual-isoform expression of human UBE3A (hUBE3A) in the developing brain. Kozak sequence engineering of our codon-optimized vector (hUBE3Aopt) enabled translation of both short and long hUBE3A protein isoforms at a near-endogenous 3:1 (short/long) ratio, a feature that could help to support optimal therapeutic outcomes. To model widespread brain delivery and early postnatal onset of hUBE3A expression, we packaged the hUBE3Aopt vector into PHP.B capsids and performed intracerebroventricular injections in neonates. This treatment significantly improved motor learning and innate behaviors in AS mice, and it rendered them resilient to epileptogenesis and associated hippocampal neuropathologies induced by seizure kindling. hUBE3A overexpression occurred frequently in the hippocampus but was uncommon in the neocortex and other major brain structures; furthermore, it did not correlate with behavioral performance. Our results demonstrate the feasibility, tolerability, and therapeutic potential for dual-isoform hUBE3A gene transfer in the treatment of AS.
Topics: Amino Acid Sequence; Angelman Syndrome; Animals; Disease Models, Animal; Humans; Mice; Seizures; Treatment Outcome; Ubiquitin-Protein Ligases
PubMed: 34676830
DOI: 10.1172/jci.insight.144712