Add Angelman Syndrome

references_cache/GEO_GSE120225.md

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+---
+reference_id: "GEO:GSE120225"
+title: Channelopathy pathogenesis in a human neural cell model of Angelman Syndrome
+content_type: summary
+---
+
+# Channelopathy pathogenesis in a human neural cell model of Angelman Syndrome
+
+## Content
+
+Angelman syndrome (AS) is a neurogenetic developmental disorder that results from the loss of E3 ubiquitin ligase UBE3A due to mutations in or deletions of the maternally inherited UBE3A allele. While mouse models of AS have implicated abnormal synaptic signaling and plasticity underlying behavioral dysfunction, how the loss of UBE3A contributes to hyperactivity of neuronal networks seen in AS patients remains unclear. Here, by utilizing human induced neurons and 3D cortical organoids derived from AS patient iPSCs and CRISPR-Cas9 mediated UBE3A KO hESCs, we uncovered a novel role of UBE3A in suppressing neuronal hyperexcitability via ubiquitin-mediated degradation of BK channels. More importantly, augmented BK channel activity in neurons manifested as increased intrinsic excitability of neurons and network level bursting and synchronization, which can be pharmacologically normalized by BK antagonists. Our study has illustrated the utility of modeling neurological diseases with human neural cells, and our results have provided new insights into underlying pathophysiological mechanisms and potential therapeutic strategy in Angelman syndrome.

references_cache/GEO_GSE12231.md

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+---
+reference_id: "GEO:GSE12231"
+title: Neonatal and embyronic CNS of mice with maternal or paternal duplication of proximal chromosomes 7 and 15
+content_type: summary
+---
+
+# Neonatal and embyronic CNS of mice with maternal or paternal duplication of proximal chromosomes 7 and 15
+
+## Content
+
+Gene expression profiling was performed on CNS tissue from neonatal mice carrying the T9H translocation and maternal or paternal duplication of proximal Chromosomes 7 and 15. Our analysis revealed the presence of two novel paternally expressed intergenic transcripts at the PWS/AS locus. The transcripts were termed Pec2 and Pec3 for paternally expressed in the CNS.Our analysis also revealed imprinting of Magel2, Mkrn3, Ndn,Ube3a and Usp29, as well as Pec2 and Pec3 in embryonic brain, 15.5 dpc, and provided a survery of biallelically expressed genes on proximal Chromosomes 7 and 15 in embryonic and neonatal CNS. This SuperSeries is composed of the SubSeries listed below.

references_cache/GEO_GSE146640.md

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+---
+reference_id: "GEO:GSE146640"
+title: Differences in transcription in Angelman syndrome and control person iPSC-derived neurons
+content_type: summary
+---
+
+# Differences in transcription in Angelman syndrome and control person iPSC-derived neurons
+
+## Content
+
+Angelman syndrome is caused by loss of funtional ubiquitin E3 ligase UBE3A and results in severe deley in cognitive and motor development. In neurons, UBE3A locates to the synapse and to the nucleus. Loss of nuclear UBE3A results in development of Angelman syndrome like symptoms in mice. UBE3A can function as transcriptional coactivator of steroid hormone receptors, but the entire function of UBE3A in the nucleus is still not clear. So we wanted to study differences in the transcriptome in neurons differentiated from iPSCs that were derived from patients with Angleman syndrome and normal controls.

references_cache/GEO_GSE160747.md

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+---
+reference_id: "GEO:GSE160747"
+title: Establishing a molecular phenotype for Angelman Syndrome stem cell-derived neurons
+content_type: summary
+---
+
+# Establishing a molecular phenotype for Angelman Syndrome stem cell-derived neurons
+
+## Content
+
+mRNAseq on (1) isogenic control and Angelman Syndrome pluripotent stem cell-derived neurons or (2) antisense oligonucleotide-treated H9 hESC-derived neurons

references_cache/GEO_GSE284678.md

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+---
+reference_id: "GEO:GSE284678"
+title: UBE3A reinstatement restores behavior and proteome in an Angelman syndrome mouse model of imprinting defects
+content_type: summary
+---
+
+# UBE3A reinstatement restores behavior and proteome in an Angelman syndrome mouse model of imprinting defects
+
+## Content
+
+Angelman Syndrome (AS) is a severe neurodevelopmental disorder with only symptomatic treatment currently available. Besides mutations within the UBE3A gene, AS is caused by deletions, imprinting center defects (mICD) or uniparental disomy of chromosome 15 (UPD). Current mouse models are Ube3a-centric and do not address expression changes of other 15q11-q13 genes on AS pathophysiology. Here, we studied a mouse line that harbors a mutation affecting the AS-PWS imprinting center, hence modeling mICD/UPD AS subtypes. mICD mice showed significant reduction in UBE3A protein, bi-allelic expression of Ube3a-ATS and Mkrn3-Snord115 gene cluster, leading to robust AS behavioral deficits and proteome alterations similar to Ube3aKO mice. Genetic UBE3A overexpression in mICD mice, mimicking therapeutic strategies that effectively activate the biallelic silenced Ube3a gene, resulted in a complete rescue of all behavioral and proteome alterations. Subsequently, treatment with an antisense oligonucleotide (ASO) to directly activate the biallelic silenced Ube3a gene in mICD mice also resulted in efficient reinstatement of UBE3A, alongside a partial rescue of behavioral phenotypes. Taken together, these findings demonstrate that UBE3A loss is the primary factor underlying AS phenotypes in the mICD/UPD mouse model, and also corroborate that UBE3A reinstatement is an attractive therapeutic strategy for mICD/UPD AS individuals.

references_cache/GEO_GSE32563.md

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+---
+reference_id: "GEO:GSE32563"
+title: Differential Gene Expression in Angelman syndrome deletion vs. int dup(15) Human Lymphocytes
+content_type: summary
+---
+
+# Differential Gene Expression in Angelman syndrome deletion vs. int dup(15) Human Lymphocytes
+
+## Content
+
+Angelman syndrome (AS) and interstitial duplication 15q autism (int dup(15)) are reciprocal genomic disorders caused by maternal deletion or duplication of the 15q11.2-q13 region. While AS is caused by maternal loss of 15q and maternal duplications of 15q can cause autism implicating the maternally expressed UBE3A gene in these phenotypes. We investigated chromatin and gene expression changes in blood and cell lines from three int dup(15) and three reciprocal AS deletion subjects to identify global genomic and gene expression changes that may influence both the AS and autism phenotypes. Using formaldehyde-assisted isolation of regulatory elements (FAIRE) we identified 1104 regions of differential open chromatin in AS deletion and 2344 regions int dup(15) indicating changes in chromatin could influence gene expression in these regions. Microarray analysis revealed 1225 genes that were elevated in AS deletion vs int dup(15) and 976 genes that were elevated in int dup(15) vs AS deletion PBMC (pvalue<0.05). Significant differences in expression were found for genes at the 15q locus like UBE3A, ATP10A and HERC2. A larger set of genes involved in chromatin remodeling, DNA repair and neurogenesis were found, at FAIRE peaks in AS deletion samples but had increased transcription in int dup(15) samples. There was a significant enhancement for genes with FOXP1 binding sites in the int dup(15) gene set and elevated FOXP1 protein could be detected in the nucleus of int dup(15) as compared to AS deletion cell lines. This analysis provides the first insights into transcriptional changes which may unveil new sets of genes and pathways contributing to both AS and autism pathogenesis.

references_cache/GEO_GSE43900.md

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+---
+reference_id: "GEO:GSE43900"
+title: Co-ordinate inhibition of autism candidate genes by topoisomerase inhibitors
+content_type: summary
+---
+
+# Co-ordinate inhibition of autism candidate genes by topoisomerase inhibitors
+
+## Content
+
+This SuperSeries is composed of the SubSeries listed below.

references_cache/PMID_14510623.md

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+---
+reference_id: "PMID:14510623"
+title: "Angelman syndrome: etiology, clinical features, diagnosis, and management of symptoms."
+authors:
+- Guerrini R
+- Carrozzo R
+- Rinaldi R
+- Bonanni P
+journal: Paediatr Drugs
+year: '2003'
+doi: 10.2165/00148581-200305100-00001
+content_type: abstract_only
+---
+
+# Angelman syndrome: etiology, clinical features, diagnosis, and management of symptoms.
+**Authors:** Guerrini R, Carrozzo R, Rinaldi R, Bonanni P
+**Journal:** Paediatr Drugs (2003)
+**DOI:** [10.2165/00148581-200305100-00001](https://doi.org/10.2165/00148581-200305100-00001)
+
+## Content
+
+1. Paediatr Drugs. 2003;5(10):647-61. doi: 10.2165/00148581-200305100-00001.
+
+Angelman syndrome: etiology, clinical features, diagnosis, and management of 
+symptoms.
+
+Guerrini R(1), Carrozzo R, Rinaldi R, Bonanni P.
+
+Author information:
+(1)Epilepsy, Neurophysiology, and Neurogenetics Unit, Institute of Child 
+Neurology and Psychiatry, University of Pisa and IRCCS Fondazione Stella Maris, 
+Pisa, Italy. renzo.guerrini@inpe.unipi.it
+
+It is estimated that Angelman syndrome (AS) accounts for up to 6% of all 
+children presenting with severe mental retardation and epilepsy. The main 
+clinical features of AS may not be apparent early in life. Clinical findings 
+present in all patients include developmental delay, which becomes apparent by 
+6-12 months of age, severely impaired expressive language, ataxic gait, 
+tremulousness of limbs, and a typical behavioral profile, including a happy 
+demeanor, hypermotoric behavior, and low attention span. Seizures, abnormal 
+electroencephalography, microcephaly, and scoliosis are observed in >80% of 
+patients. Approximately 70% of patients show a deletion involving the maternally 
+inherited chromosome 15q11-q13, encompassing a cluster of gamma-aminobutyric 
+acid receptor subunit genes, 3% show chromosome 15 paternal uniparental disomy 
+(UPD), 1% harbor a mutation in the imprinting center (a transcriptional 
+regulatory element), and 6% harbor intragenic mutations of the ubiquitin-protein 
+ligase E3A (UBE3A) gene. Twenty percent of patients have no detectable genetic 
+abnormality. Rare cases of familial recurrence of AS show either imprinting 
+center (IC) or UBE3A mutations. Approximately 75% of cases are detected through 
+the methylation test, which allows the detection of AS due to deletions, UPD and 
+IC mutations. Mutation analysis of the UBE3A gene should be performed when the 
+methylation test is negative. Individuals with chromosome 15q11-q13 deletions 
+have a more severe clinical picture and are more prone to develop severe 
+epilepsy. Epilepsy has typical features, including absence and myoclonic 
+seizures, and insidious episodes of nonconvulsive or subtle myoclonic status 
+which are easily overlooked as children appear apathetic or in a state of 
+neurologic regression. Tremulousness, present in all patients even when seizures 
+are well controlled or absent, is related to distal cortical myoclonus. Valproic 
+acid (sodium valproate), benzodiazepines, and ethosuximide, in various 
+combinations, are quite effective in treating the typical seizure types. 
+Piracetam may help in reducing distal myoclonus. Carbamazepine and vigabatrin 
+may seriously aggravate absence and myoclonic seizures and should be avoided. 
+Cognitive, language, and orthopedic problems must be addressed with vigorous 
+rehabilitation programs, including early physical therapy, which may help to 
+develop communicative skills and prevent severe scoliosis and subsequent 
+immobility. Where these treatment strategies are applied, individuals with AS 
+may reach an appreciable level of integration, self care, and have a normal life 
+span.
+
+DOI: 10.2165/00148581-200305100-00001
+PMID: 14510623 [Indexed for MEDLINE]

references_cache/PMID_20301323.md

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+---
+reference_id: "PMID:20301323"
+title: Angelman Syndrome.
+authors:
+- Adam MP
+- Bick S
+- Mirzaa GM
+- Pagon RA
+- Wallace SE
+- Amemiya A
+- Dagli AI
+- Mathews J
+- Williams CA
+year: '1993'
+content_type: abstract_only
+---
+
+# Angelman Syndrome.
+**Authors:** Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, Dagli AI, Mathews J, Williams CA
+
+## Content
+
+1. Angelman Syndrome.
+
+Dagli AI(1), Mathews J(2), Williams CA(3).
+
+In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. 
+GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 
+1993–2026.
+1998 Sep 15 [updated 2025 May 1].
+
+Author information:
+(1)Medical Genetics, Orlando Health Arnold Palmer Hospital, Orlando, Florida
+(2)Division of Genetics and Metabolism, University of North Carolina at Chapel 
+Hill, Chapel Hill, North Carolina
+(3)Division of Genetics and Metabolism, Department of Pediatrics, University of 
+Florida College of Medicine, Gainesville, Florida
+
+CLINICAL CHARACTERISTICS: Angelman syndrome (AS) is characterized by severe 
+developmental delay or intellectual disability, severe speech impairment, gait 
+ataxia and/or tremulousness of the limbs, and unique behavior with an apparent 
+happy demeanor that includes frequent laughing, smiling, and excitability. 
+Microcephaly and seizures are also common. Developmental delays are first noted 
+at around age six months; however, the unique clinical features of AS do not 
+become manifest until after age one year.
+DIAGNOSIS/TESTING: The diagnosis of AS is established in a proband who meets the 
+consensus clinical diagnostic criteria and/or who has findings on molecular 
+genetic testing that suggest deficient expression or function of the maternally 
+inherited UBE3A allele. Analysis of parent-specific DNA methylation imprints in 
+the 15q11.2-q13 chromosome region detects approximately 80% of individuals with 
+AS, including those with a deletion, uniparental disomy, or an imprinting 
+defect; fewer than 1% of individuals have a cytogenetically visible chromosome 
+rearrangement (e.g., translocation or inversion). UBE3A sequence analysis 
+detects pathogenic variants in an additional approximately 11% of individuals. 
+Therefore, molecular genetic testing (methylation analysis and UBE3A sequence 
+analysis) identifies alterations in approximately 90% of individuals. The 
+remaining 10% of individuals with classic phenotypic features of AS have the 
+disorder as a result of an as-yet unidentified genetic mechanism.
+MANAGEMENT: Treatment of manifestations: Anti-seizure medication for seizures. 
+Accommodation for hypermotoric behaviors and disruptive nighttime wakefulness. 
+Behavior modification can be effective for disruptive or self-injurious 
+behaviors. Physical therapy, occupational therapy, and speech therapy with an 
+emphasis on nonverbal methods of communication, including augmentative 
+communication aids (e.g., picture cards, communication boards) and signing. 
+Individualization and flexibility in school settings. Routine management of 
+gastroesophageal reflux, feeding difficulties, constipation, and strabismus. 
+Thoraco-lumbar jackets and/or surgical intervention for scoliosis. Bracing or 
+surgery as needed for subluxed or pronated ankles or tight Achilles tendons. 
+Surveillance: Monitor for new seizures and/or changes in seizures, developmental 
+progress, behavior issues, mobility, motor skills, gastroesophageal reflux, 
+constipation, and feeding issues at each visit. Evaluation of older children for 
+obesity associated with an excessive appetite. Annual clinical examination for 
+scoliosis; ophthalmology examination in the first year if strabismus is present; 
+ophthalmology exam at age two years with follow up per ophthalmologist; clinical 
+examination for scoliosis annually. Agents/circumstances to avoid: Overtreatment 
+with sedating medications in order to reduce hyperexcitable and hypermotoric 
+behavior. Overtreatment with anti-seizure medication when movement abnormalities 
+are mistaken for seizures and/or when EEG abnormalities persist even as seizures 
+are controlled.
+GENETIC COUNSELING: Individuals with AS typically represent simplex cases (i.e., 
+a single affected family member) and have the disorder as the result of a de 
+novo genetic alteration associated with a very low recurrence risk. Less 
+commonly, an individual with AS has the disorder as the result of a genetic 
+alteration associated with an imprinting pattern of autosomal dominant 
+inheritance or variable recurrence risk. Reliable recurrence risk assessment 
+therefore requires identification of the underlying genetic mechanism in the 
+proband and confirmation of the genetic status of the parents. Prenatal 
+detection of all the known molecular genetic alterations in the 15q11.2-q13 
+region that give rise to AS is possible and is an option for families once the 
+underlying genetic mechanism in the proband has been identified.
+
+Copyright © 1993-2026, University of Washington, Seattle. GeneReviews is a 
+registered trademark of the University of Washington, Seattle. All rights 
+reserved.
+
+PMID: 20301323

references_cache/PMID_20398390.md

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+---
+reference_id: "PMID:20398390"
+title: Epilepsy in patients with Angelman syndrome.
+authors:
+- Fiumara A
+- Pittalà A
+- Cocuzza M
+- Sorge G
+journal: Ital J Pediatr
+year: '2010'
+doi: 10.1186/1824-7288-36-31
+content_type: abstract_only
+---
+
+# Epilepsy in patients with Angelman syndrome.
+**Authors:** Fiumara A, Pittalà A, Cocuzza M, Sorge G
+**Journal:** Ital J Pediatr (2010)
+**DOI:** [10.1186/1824-7288-36-31](https://doi.org/10.1186/1824-7288-36-31)
+
+## Content
+
+1. Ital J Pediatr. 2010 Apr 16;36:31. doi: 10.1186/1824-7288-36-31.
+
+Epilepsy in patients with Angelman syndrome.
+
+Fiumara A(1), Pittalà A, Cocuzza M, Sorge G.
+
+Author information:
+(1)Pediatric Neurology, Regional Referral Centre for Inborn Errors Metabolism, 
+University of Catania, Italy. agafiu@virgilio.it
+
+Angelman syndrome (AS) is a neuro-behavioural, genetically determined condition, 
+characterized by ataxic jerky movements, happy sociable disposition and 
+unprovoked bouts of laughter in association with seizures, learning disabilities 
+and language impairment. Most of the cases are hardly diagnosed during infancy 
+as jerky movements, the cardinal sign, appear later in childhood. AS is caused 
+by a variety of genetic mechanisms involving the 15q 11-13 chromosome. About 70% 
+of cases are due to a "de novo" interstitial deletion in the long arm region, 
+arising on the maternally inherited chromosome. The diagnosis is confirmed by 
+methylation test or by mutation analysis of UBE3A gene. The deletion phenotype 
+is generally linked to a more severe clinical picture in that 95% of patients 
+manifest more severe seizures, severe mental and motor retardation, dysmorphic 
+features and microcephaly.The pathogenesis of epilepsy in AS is still not fully 
+understood. The presence in the commonly deleted region of a cluster of genes 
+coding for 3 subunits of the GABAa receptor complex has lead to the hypothesis 
+that GABA neurotransmission is involved. Epilepsy, often severe and hard to 
+control, is present in 85% of patients within the first three years of life, 
+although less than 25% develop seizures during the first year. It was observed 
+that febrile seizures often precede the diagnosis. Most frequent types are 
+atypical absences, generalized tonic-clonic, atonic or myoclonic seizures, with 
+multiple seizure types occurring in 50% of deleted patients. There is still some 
+doubt about the association with West syndrome. The EEG abnormalities are not 
+themselves pathognomonic of AS and both background activity and epileptic 
+discharges vary even in the same patient with time. Nevertheless, the existence 
+of some suggestive patterns should facilitate the early diagnosis allowing the 
+correct genetic counselling for the family. Some drugs seems to act better than 
+others, Valproate, ethosuximide and clonazepam giving the best results.
+
+DOI: 10.1186/1824-7288-36-31
+PMCID: PMC2865483
+PMID: 20398390 [Indexed for MEDLINE]