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ENeuro 2021Angelman syndrome (AS) is a neurodevelopmental disorder with unique behavioral phenotypes, seizures, and distinctive electroencephalographic (EEG) patterns. Recent...
Angelman syndrome (AS) is a neurodevelopmental disorder with unique behavioral phenotypes, seizures, and distinctive electroencephalographic (EEG) patterns. Recent studies identified motor, social communication, and learning and memory deficits in a CRISPR engineered rat model with a complete maternal deletion of the gene. It is unknown whether this model recapitulates other aspects of the clinical disorder. We report here the effect of maternal deletion in the rat on epileptiform activity, seizure threshold, and quantitative EEG. Using video-synchronized EEG (vEEG) monitoring, we assessed spectral power and epileptiform activity early postnatally through adulthood. While EEG power was similar to wild-type (WT) at 1.5 weeks postnatally, at all other ages analyzed, our findings were similar to the AS phenotype in mice and humans with significantly increased δ power. Analysis of epileptiform activity in juvenile and adult rats showed increased time spent in epileptiform activity in AS compared with WT rats. We evaluated seizure threshold using pentylenetetrazol (PTZ), audiogenic stimulus, and hyperthermia to provoke febrile seizures (FSs). Behavioral seizure scoring following PTZ induction revealed no difference in seizure threshold in AS rats, however behavioral recovery from the PTZ-induced seizure was longer in the adult group with significantly increased hippocampal epileptiform activity during this phase. When exposed to hyperthermia, AS rat pups showed a significantly lower temperature threshold to first seizure than WT. Our findings highlight an age-dependence for the EEG and epileptiform phenotypes in a preclinical model of AS, and support the use of quantitative EEG and increased δ power as a potential biomarker of AS.
Topics: Angelman Syndrome; Animals; Electroencephalography; Gene Deletion; Mice; Phenotype; Rats; Seizures; Ubiquitin-Protein Ligases
PubMed: 33531368
DOI: 10.1523/ENEURO.0345-20.2020 -
Seizure Apr 2008Angelman syndrome is a neurogenetic disorder caused by lack of UBE3A gene expression from the maternally inherited chromosome 15 due to various 15q11-q13 abnormalities.... (Review)
Review
Angelman syndrome is a neurogenetic disorder caused by lack of UBE3A gene expression from the maternally inherited chromosome 15 due to various 15q11-q13 abnormalities. In addition to severe developmental delay, virtual absence of speech, motor impairment, a behavioural phenotype that includes happy demeanor, and distinctive rhythmic electroencephalographic features, over 90% of patients have epilepsy. Many different seizure types may occur, atypical absences and myoclonic seizures being particularly prevalent. Non-convulsive status epilepticus is common, sometimes in the context of the epileptic syndrome referred to as myoclonic status in non-progressive encephalopathies. Epilepsy predominates in childhood, but may persist or reappear in adulthood. Management is difficult in a proportion of patients. It might be improved by better understanding of pathophysiology. Current hypotheses involve abnormal inhibitory transmission due to impaired regulation of GABAA receptors related to functional absence of UBE3A and abnormal hippocampal CaMKII activity.
Topics: Angelman Syndrome; Electroencephalography; Epilepsy; Humans; Valproic Acid
PubMed: 17904873
DOI: 10.1016/j.seizure.2007.08.004 -
Child Psychiatry and Human Development Aug 2021Angelman syndrome (AS) is a complex, heterogeneous, and life-long neurodevelopmental disorder. Despite the considerable impact on individuals and caregivers, no...
Angelman syndrome (AS) is a complex, heterogeneous, and life-long neurodevelopmental disorder. Despite the considerable impact on individuals and caregivers, no disease-modifying treatments are available. To support holistic clinical management and the development of AS-specific outcome measures for clinical studies, we conducted primary and secondary research identifying the impact of symptoms on individuals with AS and their unmet need. This qualitative research adopted a rigorous step-wise approach, aggregating information from published literature, then evaluating it via disease concept elicitation interviews with clinical experts and caregivers. We found that the AS-defining concepts most relevant for treatment included: impaired expressive communication, seizures, maladaptive behavior, cognitive impairment, motor function difficulties, sleep disturbance, and limited self-care abilities. We highlight the relevance of age in experiencing these key AS concepts, and the difference between the perceptions of clinicians and caregivers towards the syndrome. Finally, we outline the impact of AS on individuals, caregivers, and families.
Topics: Angelman Syndrome; Caregivers; Humans; Models, Theoretical; Patient-Centered Care; Qualitative Research
PubMed: 32880036
DOI: 10.1007/s10578-020-01051-z -
Molecular Psychiatry Jul 2021Angelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair UBE3A...
Angelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair UBE3A expression, but they differ in how neighboring genes on chromosome 15 at 15q11-q13 are affected. There is evidence that different genetic subtypes present with different clinical severity, but a systematic quantitative investigation is lacking. Here we analyze natural history data on a large sample of individuals with AS (n = 250, 848 assessments), including clinical scales that quantify development of motor, cognitive, and language skills (Bayley Scales of Infant Development, Third Edition; Preschool Language Scale, Fourth Edition), adaptive behavior (Vineland Adaptive Behavioral Scales, Second Edition), and AS-specific symptoms (AS Clinical Severity Scale). We found that clinical severity, as captured by these scales, differs between genetic subtypes: individuals with UBE3A pathogenic variants and imprinting defects (IPD) are less affected than individuals with uniparental paternal disomy (UPD); of those with UBE3A pathogenic variants, individuals with truncating mutations are more impaired than those with missense mutations. Individuals with a deletion that encompasses UBE3A and other genes are most impaired, but in contrast to previous work, we found little evidence for an influence of deletion length (class I vs. II) on severity of manifestations. The results of this systematic analysis highlight the relevance of genomic regions beyond UBE3A as contributing factors in the AS phenotype, and provide important information for the development of new therapies for AS. More generally, this work exemplifies how increasing genetic irregularities are reflected in clinical severity.
Topics: Angelman Syndrome; Chromosomes, Human, Pair 15; Genomic Imprinting; Genotype; Humans; Phenotype; Ubiquitin-Protein Ligases
PubMed: 32792659
DOI: 10.1038/s41380-020-0858-6 -
Nature Nov 2020Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a mutation or deletion of the maternally inherited UBE3A allele. In neurons, the paternally...
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a mutation or deletion of the maternally inherited UBE3A allele. In neurons, the paternally inherited UBE3A allele is silenced in cis by a long non-coding RNA called UBE3A-ATS. Here, as part of a systematic screen, we found that Cas9 can be used to activate ('unsilence') paternal Ube3a in cultured mouse and human neurons when targeted to Snord115 genes, which are small nucleolar RNAs that are clustered in the 3' region of Ube3a-ATS. A short Cas9 variant and guide RNA that target about 75 Snord115 genes were packaged into an adeno-associated virus and administered to a mouse model of AS during the embryonic and early postnatal stages, when the therapeutic benefit of restoring Ube3a is predicted to be greatest. This early treatment unsilenced paternal Ube3a throughout the brain for at least 17 months and rescued anatomical and behavioural phenotypes in AS mice. Genomic integration of the adeno-associated virus vector into Cas9 target sites caused premature termination of Ube3a-ATS at the vector-derived polyA cassette, or when integrated in the reverse orientation, by transcriptional collision with the vector-derived Cas9 transcript. Our study shows that targeted genomic integration of a gene therapy vector can restore the function of paternally inherited UBE3A throughout life, providing a path towards a disease-modifying treatment for a syndromic neurodevelopmental disorder.
Topics: Angelman Syndrome; Animals; CRISPR-Associated Protein 9; CRISPR-Cas Systems; Dependovirus; Disease Models, Animal; Female; Gene Editing; Gene Silencing; Genetic Therapy; Genetic Vectors; Humans; Male; Mice; Mice, Inbred C57BL; Nervous System; Paternal Inheritance; Phenotype; RNA, Long Noncoding; Ubiquitin-Protein Ligases
PubMed: 33087932
DOI: 10.1038/s41586-020-2835-2 -
BMJ Case Reports Oct 2011Happy Puppet syndrome is characterised by a partial deficit of paired autosomal chromosome 15. It is a neuro-genetic disorder characterised by intellectual and...
Happy Puppet syndrome is characterised by a partial deficit of paired autosomal chromosome 15. It is a neuro-genetic disorder characterised by intellectual and developmental delay, sleep disturbance, seizures, jerky movements (especially hand-flapping), frequent laughter or smiling and usually a happy demeanour. It is also called as Angelman syndrome (AS). People with AS are sometimes known as 'angels', both because of the syndrome's name and because of their youthful, happy appearance. A 6.5-year-old girl is presented and clinical suspicion of AS was raised at the age of 4 years when she presented with mental retardation and epilepsy, absence of speech, inability to gait and unprovoked episodes of laughter. Fluorescent in situ hybridisation chromosomal analysis revealed micro deletion on the maternally derived allele of 15q chromosome.
Topics: Angelman Syndrome; Child; Chromosome Aberrations; Chromosomes, Human, Pair 15; Dental Caries; Dental Restoration Repair; Female; Glass Ionomer Cements; Humans
PubMed: 22675103
DOI: 10.1136/bcr.09.2011.4747 -
A Conceptual Model of Angelman Syndrome and Review of Relevant Clinical Outcomes Assessments (COAs).The Patient Feb 2019Angelman syndrome (AS) is a rare, neurological genetic disorder for which no clinical outcomes assessments (COAs) or conceptual models (CM) have been developed.
BACKGROUND
Angelman syndrome (AS) is a rare, neurological genetic disorder for which no clinical outcomes assessments (COAs) or conceptual models (CM) have been developed.
OBJECTIVE
This study aimed to identify symptoms and impacts relevant and important in this patient population and develop a conceptual model of AS, and to evaluate the content validity of selected COA instruments with potential for inclusion in clinical studies of AS to capture treatment benefit.
METHODS
For both concept elicitation (CE) and cognitive interviews (CI), caregivers of children, adolescents, and adults with AS and clinicians with AS experience were targeted. For CI, clinicians discussed the Modified Performance-Oriented Mobility Assessment (MPOMA-G) and ProtoKinetics Zeno Walkway™ and caregivers reviewed the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT), the Anxiety, Depression and Mood Scale (ADAMS), the Aberrant Behavior Checklist-Community (ABC-C), and the Morning Diary.
RESULTS
Four clinicians and 34 caregivers participated in CE interviews; three clinicians and 36 caregivers participated in CI. A conceptual model, initially informed by literature, was refined based on interview data. Five domains of symptoms, signs, and characteristics of AS were identified: cognitive and executive functioning, social-emotional, emotional-expressive behavior, sensory-compulsive behavior, and physical. Patient impacts were identified in three domains: activities of daily living, school, and social/community. Caregiver impacts were identified in five domains: mental health, physical health, work, home, and social. While all instruments demonstrated the ability to provide relevant data for the AS population, each instrument either contained some items irrelevant to individuals with AS or was missing important concepts based on the interviews. No single instrument covered all relevant domains specific to AS.
CONCLUSION
Future work should consider the adaptation of existing COAs and the development of a novel AS-specific instrument for use in clinical research to ensure outcomes important to this patient population are captured.
Topics: Adolescent; Adult; Angelman Syndrome; Caregivers; Child; Concept Formation; Cost of Illness; Female; Humans; Interviews as Topic; Male; Middle Aged; Outcome Assessment, Health Care; Qualitative Research; Young Adult
PubMed: 29987743
DOI: 10.1007/s40271-018-0323-7 -
Nature Communications Mar 2023Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability and atypical behaviors. AS results from loss of expression of the E3...
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.
Topics: Animals; Female; Humans; Male; Mice; Alleles; Angelman Syndrome; Disease Models, Animal; Intellectual Disability; Ion Channels; Linoleic Acid
PubMed: 36859399
DOI: 10.1038/s41467-023-36818-0 -
European Journal of Human Genetics :... Nov 2009Angelman syndrome (AS) is a distinct neurogenetic syndrome, first described in 1965. The phenotype is well known in infancy and adulthood, but the clinical features may... (Review)
Review
Angelman syndrome (AS) is a distinct neurogenetic syndrome, first described in 1965. The phenotype is well known in infancy and adulthood, but the clinical features may change with age. The main clinical characteristics include severe mental retardation, epileptic seizures and EEG abnormalilties, neurological problems and distinct facial dysmorphic features. Behavioural problems such as hyperactivity and sleeping problems are reported, although these patients present mostly a happy personality with periods of inappropriate laughter. Different underlying genetic mechanisms may cause AS, with deletion of chromosome 15 as the most frequent cause. Other genetic mechanisms such as paternal uniparental disomy, imprinting defect and mutation in the UBE3A gene are present in smaller groups of patients with AS. As the recurrence risk can be up to 50%, the clinical diagnosis of AS should be confirmed by laboratory tesing, and genetic counselling should be provided. Treatment of seizures, physical therapy or other intervention strategies are helpful to ameliorate the symptoms.
Topics: Angelman Syndrome; Diagnosis, Differential; Genetic Counseling; Humans
PubMed: 19455185
DOI: 10.1038/ejhg.2009.67 -
The Journal of Clinical Investigation Dec 2019Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, lack of speech, ataxia, EEG abnormalities, and epilepsy. Seizures in...
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, lack of speech, ataxia, EEG abnormalities, and epilepsy. Seizures in individuals with AS are common, debilitating, and often drug resistant. Thus, there is an unmet need for better treatment options. Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, has shown antiseizure activity and behavioral benefits in preclinical and clinical studies for some disorders associated with epilepsy, suggesting that the same could be true for AS. Here, we show that acute CBD (100 mg/kg) treatment attenuated hyperthermia- and acoustically induced seizures in a mouse model of AS. However, neither acute CBD nor a 2-week-long course of CBD administered immediately after a kindling protocol could halt the proepileptogenic plasticity observed in AS model mice. CBD had a dose-dependent sedative effect but did not have an impact on motor performance. CBD abrogated the enhanced intracortical local field potential power, including the delta and theta rhythms observed in AS model mice, indicating that CBD administration could also help normalize the EEG deficits observed in individuals with AS. We believe our results provide critical preclinical evidence supporting CBD treatment of seizures and alleviation of EEG abnormalities in AS and will thus help guide the rational development of CBD as a treatment for AS.
Topics: Angelman Syndrome; Animals; Cannabidiol; Disease Models, Animal; Electroencephalography; Female; Male; Mice; Mice, Inbred C57BL; Seizures
PubMed: 31503547
DOI: 10.1172/JCI130419