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Angelman Syndrome

Angelman Syndrome (MONDO:0007113) — Disease Characteristics Research Report

2026-04-25
Falcon MONDO:0007113 Model: Edison Scientific Literature 44 citations

Angelman Syndrome (MONDO:0007113) — Disease Characteristics Research Report

Executive summary

Angelman syndrome (AS) is a rare, severe neurodevelopmental disorder caused by loss of functional maternal UBE3A expression in neurons, while the paternal allele is normally silenced by a neuronally expressed antisense transcript (UBE3A-ATS). The disorder is characterized by profound developmental delay/intellectual disability, minimal-to-absent speech, ataxia/gait disturbance, seizures, sleep disturbance, and a distinctive behavioral phenotype (frequent laughter/happy demeanor). Recent (2023–2024) research has accelerated disease-modifying strategies that restore UBE3A function, especially by unsilencing paternal UBE3A using antisense oligonucleotides (ASOs), RNA-targeting CRISPR/Cas13, and small-molecule “unsilencers.” Key translational biomarkers include quantitative EEG delta-band power, coherence, and sleep spindle metrics.

1. Disease information

1.1 Definition and overview

Angelman syndrome is a rare neurodevelopmental disorder due to maternal UBE3A deficiency in neurons; because paternal UBE3A is epigenetically silenced in neurons by UBE3A-ATS, loss of the maternal allele produces near-absence of UBE3A protein in the brain and the clinical phenotype. (roberts2024epigeneticsinrare pages 12-14, yang2021genotype–phenotypecorrelationsin pages 1-2)

Abstract-supported quote (overview of core mechanism): “Angelman syndrome … is caused by maternal UBE3A deficiency. A promising therapeutic approach … is to reactivate the intact paternal UBE3A by suppressing UBE3A-ATS.” (lee2023antisenseoligonucleotidetherapy pages 1-4)

1.2 Key identifiers

1.3 Synonyms / alternative names

Commonly used synonyms in the literature include “Angelman syndrome,” “AS,” and descriptions historically referring to the characteristic behavior (e.g., “happy disposition”). (roberts2024epigeneticsinrare pages 12-14, yang2021genotype–phenotypecorrelationsin pages 1-2)

1.4 Evidence provenance (individual vs aggregated)

The report’s disease characterization draws from: - Aggregated resources/reviews (mechanism, genotype proportions, diagnostic algorithms, therapy landscape) (roberts2024epigeneticsinrare pages 12-14, yang2021genotype–phenotypecorrelationsin pages 1-2, ma2023praderwilliandangelman pages 2-5) - Human cohort/natural history datasets (genotype-stratified epilepsy and EEG phenotypes) (cassater2021clinicalcharacterizationof pages 1-3, frohlich2019electrophysiologicalphenotypein pages 1-3) - Preclinical model systems (mouse, rat, nonhuman primate, stem-cell/iPSC models) supporting mechanism and intervention timing (born2021earlydevelopmentaleeg pages 1-2, ramirez2024regionalandcellular pages 1-2, santos2023stemcellmodels pages 10-11)

2. Etiology

2.1 Primary causal factors

AS is a Mendelian imprinting disorder due to loss of maternal UBE3A function in neurons, with paternal UBE3A silenced by UBE3A-ATS. (roberts2024epigeneticsinrare pages 12-14, yang2021genotype–phenotypecorrelationsin pages 1-2, lee2023antisenseoligonucleotidetherapy pages 1-4)

Mechanistic detail relevant to etiology: UBE3A-ATS represses paternal UBE3A “in cis through a transcriptional collision mechanism,” explaining why reactivating the paternal allele is a rational therapy. (lee2023antisenseoligonucleotidetherapy pages 1-4)

2.2 Genetic risk factors (causal variants / molecular subtypes)

Major molecular etiologies and approximate frequencies reported across reviews/cohorts include: - Maternal 15q11–q13 deletion: ~70% (yang2021genotype–phenotypecorrelationsin pages 1-2) (some reviews report higher/variable values) (markati2021therapiesinpreclinical pages 1-3) - Paternal uniparental disomy (UPD) 15: ~2–7% (yang2021genotype–phenotypecorrelationsin pages 1-2) - Imprinting defects (IC defects): ~3–5% (yang2021genotype–phenotypecorrelationsin pages 1-2) - Pathogenic UBE3A variants (coding mutations): ~10% (yang2021genotype–phenotypecorrelationsin pages 1-2)

A 2024 epigenetics-focused review also summarizes subtype ranges and highlights a “large (5–7 Mb) maternal deletion,” with UPD (3–7%), imprinting defects (2–4%), and UBE3A coding mutations (~10%). (roberts2024epigeneticsinrare pages 12-14)

2.3 Environmental risk factors and protective factors

AS is primarily genetic; no environmental risk factors or protective factors were identified in the retrieved evidence corpus.

2.4 Gene–environment interactions

No specific gene–environment interaction evidence was identified in the retrieved corpus.

3. Phenotypes

3.1 Core phenotype domains (with suggested HPO terms)

Below are key phenotypes, typical timing, and representative HPO term suggestions.

1) Global developmental delay / severe intellectual disability - Typical onset: infancy/early childhood; often apparent in the first year of life. (yang2021genotype–phenotypecorrelationsin pages 1-2, alias2023angelmansyndromea pages 1-2) - Suggested HPO: HP:0001263 (Global developmental delay), HP:0001249 (Intellectual disability)

2) Severe expressive speech impairment / absent speech - Minimal-to-absent expressive language is a hallmark. (roberts2024epigeneticsinrare pages 12-14, yang2021genotype–phenotypecorrelationsin pages 1-2) - Suggested HPO: HP:0001344 (Absent speech), HP:0002465 (Poor speech)

3) Movement disorder: ataxia / gait disturbance / tremor - Characteristic unsteady gait and balance problems; jerky movements. (roberts2024epigeneticsinrare pages 12-14, yang2021genotype–phenotypecorrelationsin pages 1-2) - Suggested HPO: HP:0001251 (Ataxia), HP:0002066 (Gait ataxia), HP:0001337 (Tremor)

4) Epilepsy and seizure types - Many individuals develop seizures early; one review states seizures begin in “>80% before age three.” (roberts2024epigeneticsinrare pages 12-14) - Natural history cohort data show strong genotype effects: in 265 children, epilepsy was more common in deletion vs non-deletion genotypes (171/187 [91%] vs 48/78 [61%]) and with earlier median onset (24 vs 57 months). (cassater2021clinicalcharacterizationof pages 1-3) - Suggested HPO: HP:0001250 (Seizures), HP:0002184 (Focal seizures) / HP:0002197 (Generalized seizures) as appropriate

5) Sleep disturbance - Sleep problems are prominent; preclinical and clinical EEG work supports sleep-architecture disruptions. (lee2023antisenseoligonucleotidetherapy pages 1-4, bakker2018abnormalcoherenceand pages 1-2) - Suggested HPO: HP:0002360 (Sleep disturbance)

6) Behavioral phenotype (happy demeanor / frequent laughter) - Distinctive behavioral profile includes frequent inappropriate laughter/happy disposition. (roberts2024epigeneticsinrare pages 12-14, yang2021genotype–phenotypecorrelationsin pages 1-2) - Suggested HPO: HP:0000749 (Inappropriate laughter)

3.2 EEG phenotypes and quantitative biomarkers (key statistics)

EEG abnormalities are a defining clinical biomarker domain in AS.

  • Elevated broadband power peaking in delta range: In a genotype-stratified study (deletion n=37, non-deletion n=21, controls n=48), both genotypes showed “excess broadband power from 1–32 Hz peaking in the delta range (peak 2.8 Hz).” (frohlich2019electrophysiologicalphenotypein pages 1-3)
  • Genotype-specific spectral differences: deletion AS showed elevated theta (peak 5.3 Hz) and diminished beta (peak 23 Hz) relative to non-deletion AS, implicating hemizygosity of the GABRB3–GABRA5–GABRG3 cluster within typical deletions. (frohlich2019electrophysiologicalphenotypein pages 1-3)
  • Sleep EEG architecture and connectivity: In a retrospective EEG study (28 AS vs 72 neurotypical controls; ages 4–11), AS showed increased long-range coherence (wake across frequencies; sleep gamma coherence) and fewer/shorter sleep spindles. (bakker2018abnormalcoherenceand pages 1-2)
  • Longitudinal EEG delta modeling for trials: A natural history modeling study used 204 EEG recordings from 56 subjects (ages 1.3–21) to predict delta (2–4 Hz) trajectories and showed, in mice, ASO treatment effects detectable through at least 8 weeks (P < 1e-15) with correlation to Ube3a expression (P < 0.001). (spencer2022longitudinaleegmodel pages 1-3)

3.3 Quality of life (QoL) impact

QoL limitations arise from severe developmental disability, communication impairment, seizures/sleep disruption, and motor dysfunction, driving a need for multidisciplinary supports and accessible outcome measures. (ma2023praderwilliandangelman pages 2-5, bakker2018abnormalcoherenceand pages 1-2)

4. Genetic / molecular information

4.1 Causal genes

  • UBE3A (ubiquitin protein ligase E3A): primary causal gene underlying AS when maternal neuronal expression is lost. (roberts2024epigeneticsinrare pages 12-14, yang2021genotype–phenotypecorrelationsin pages 1-2)

4.2 Pathogenic variant classes and structural mechanisms

Major causal mechanisms include: - Maternal 15q11–q13 deletions (often ~5–7 Mb): remove maternal UBE3A and can remove additional genes contributing to phenotype severity (notably GABA-A receptor subunit genes). (roberts2024epigeneticsinrare pages 12-14, cassater2021clinicalcharacterizationof pages 1-3) - Paternal UPD 15 and imprinting center defects: disrupt parent-of-origin expression (methylation) leading to lack of maternal UBE3A expression in neurons. (roberts2024epigeneticsinrare pages 12-14, ma2023praderwilliandangelman pages 2-5) - Intragenic UBE3A variants: missense, nonsense, splice, small indels; sequencing is required when methylation is normal. (ma2023praderwilliandangelman pages 2-5, yang2021genotype–phenotypecorrelationsin pages 2-4)

4.3 Functional consequence

The unifying functional consequence is loss-of-function of maternal UBE3A activity in neurons due to imprinting, with paternal allele silenced by UBE3A-ATS. (lee2023antisenseoligonucleotidetherapy pages 1-4, roberts2024epigeneticsinrare pages 12-14)

4.4 Epigenetic information (imprinting)

Imprinting is central: in neurons the paternal UBE3A allele is silenced by UBE3A-ATS; restoring expression is a main disease-modifying strategy. (lee2023antisenseoligonucleotidetherapy pages 1-4, roberts2024epigeneticsinrare pages 12-14)

Mechanism schematic evidence (figure): A schematic of UBE3A imprinting and UBE3A-ATS-mediated silencing in mature neurons is shown in Vihma et al. 2024. (vihma2024ube3aunsilencerfor media f576f803)

4.5 Modifier genes / locus context

Deletion genotypes can include hemizygosity of GABRB3, GABRA5, and GABRG3, proposed contributors to more severe epilepsy/EEG features relative to non-deletion genotypes. (cassater2021clinicalcharacterizationof pages 1-3, frohlich2019electrophysiologicalphenotypein pages 1-3)

5. Environmental information

AS is primarily genetic; environmental/lifestyle and infectious triggers were not identified as causal contributors in this evidence set.

6. Mechanism / pathophysiology

6.1 Causal chain (from genotype to phenotype)

1) Initial trigger: maternal UBE3A deletion/mutation, paternal UPD, or imprinting defect reduces/abolishes maternal UBE3A expression in neurons. (roberts2024epigeneticsinrare pages 12-14, yang2021genotype–phenotypecorrelationsin pages 1-2) 2) Upstream epigenetic constraint: paternal UBE3A is silenced in neurons by UBE3A-ATS; thus neurons have insufficient UBE3A protein. (lee2023antisenseoligonucleotidetherapy pages 1-4, roberts2024epigeneticsinrare pages 12-14) 3) Downstream circuit dysfunction: abnormal neuronal synchrony and network activity manifests as characteristic EEG signatures (elevated delta power, altered coherence, reduced spindles), contributing to epilepsy, sleep disruption, and cognitive impairment. (frohlich2019electrophysiologicalphenotypein pages 1-3, bakker2018abnormalcoherenceand pages 1-2, spencer2022longitudinaleegmodel pages 1-3) 4) Clinical manifestations: severe developmental delay/ID, minimal speech, ataxia, seizures, sleep disturbance, and behavioral features. (roberts2024epigeneticsinrare pages 12-14, yang2021genotype–phenotypecorrelationsin pages 1-2)

6.2 Molecular pathways and cellular processes (selected, model-supported)

A 2023 stem-cell model review summarizes downstream abnormalities identified largely in animal models, including dysregulated mTOR signaling, synaptic plasticity deficits, mitochondrial dysfunction, and oxidative stress/ROS, as well as epilepsy linked to GABAergic circuitry dysfunction. (santos2023stemcellmodels pages 8-9)

Suggested GO biological process terms (representative): - Synaptic plasticity: GO:0048167 - Regulation of synaptic transmission: GO:0050804 - Ubiquitin-dependent protein catabolic process: GO:0006511 - mTOR signaling: GO:0031929 (regulation of mTOR signaling)

Suggested CL cell types (representative): - Neuron: CL:0000540 - GABAergic interneuron: CL:0000617 (as relevant to GABAergic circuitry discussions) - Glial cells (for imprinting contrast): astrocyte CL:0000127, oligodendrocyte CL:0000128

7. Anatomical structures affected

7.1 Organ/system level

Primary involvement is the central nervous system, reflected in neurodevelopmental disability, epilepsy, sleep dysregulation, and motor dysfunction. (roberts2024epigeneticsinrare pages 12-14, frohlich2019electrophysiologicalphenotypein pages 1-3)

Suggested UBERON terms: - Brain: UBERON:0000955 - Cerebral cortex: UBERON:0000956 - Hippocampus: UBERON:0001954

7.2 Tissue and cellular level

Evidence indicates paternal UBE3A silencing occurs in neurons but not glial cells, at least in rhesus macaque developmental mapping, supporting neuron-targeted interventions. (ramirez2024regionalandcellular pages 1-2)

7.3 Subcellular

UBE3A is an E3 ubiquitin ligase; dysfunction impacts ubiquitin-mediated processes and downstream nuclear/cytoplasmic neuronal function (broadly summarized in the therapeutics literature). (markati2021therapiesinpreclinical pages 1-3)

Suggested GO cellular component terms (representative): - Nucleus: GO:0005634 - Synapse: GO:0045202

8. Temporal development

8.1 Onset

Clinical features typically emerge in infancy/early childhood; seizures often begin early (one review: >80% before age 3). (roberts2024epigeneticsinrare pages 12-14)

Cohort data show genotype-dependent timing: median seizure onset 24 months (deletion) vs 57 months (non-deletion). (cassater2021clinicalcharacterizationof pages 1-3)

8.2 Progression/course

AS is typically lifelong; symptom domains evolve with development. EEG delta power varies with age, motivating longitudinal models for clinical trials. (spencer2022longitudinaleegmodel pages 1-3)

8.3 Critical windows for intervention

While early-life treatment is widely viewed as optimal, preclinical data suggest at least some phenotypes (EEG rhythms and sleep disturbance) may be improved even with juvenile/adult ASO intervention.

Abstract-supported quote: “reducing Ube3a-ATS by antisense oligonucleotides in juvenile or adult … mice rescues the abnormal electroencephalogram rhythms and sleep disturbance” (lee2023antisenseoligonucleotidetherapy pages 1-4).

Nonhuman primate mapping indicates paternal UBE3A silencing onset between gestational day 48 and 100 in macaque neurons, supporting early (potentially prenatal) intervention concepts. (ramirez2024regionalandcellular pages 1-2)

9. Inheritance and population

9.1 Epidemiology

Reported frequency is consistently rare but variable across sources: - Prevalence estimates in reviews span roughly 1 in 10,000–24,000 births. (yang2021genotype–phenotypecorrelationsin pages 1-2) - Other sources commonly cite ~1 in 12,000–20,000. (roberts2024epigeneticsinrare pages 12-14, alias2023angelmansyndromea pages 1-2)

9.2 Inheritance pattern

Although AS is genetic, most common mechanisms (large maternal deletions, UPD) are typically de novo; recurrence risk depends strongly on molecular subtype (e.g., imprinting center defects and inherited UBE3A variants can elevate recurrence risk). Molecular subtyping is therefore essential in genetic counseling. (ma2023praderwilliandangelman pages 2-5, roberts2024epigeneticsinrare pages 12-14)

9.3 Sex ratio, geography, variant geography

Not available in the retrieved evidence corpus.

10. Diagnostics

10.1 Molecular diagnostic workflow (real-world implementation)

A consistent algorithm across reviews emphasizes methylation/copy-number first: - First-line: methylation analysis of 15q11–q13 (e.g., SNRPN locus) and/or MS-MLPA, which can assess methylation + copy number and detect microdeletions and mosaicism. (ma2023praderwilliandangelman pages 2-5) - If methylation abnormal + deletion present: AS due to 15q11–q13 deletion. (yang2021genotype–phenotypecorrelationsin pages 2-4) - If methylation abnormal without deletion: use microsatellite linkage analysis to distinguish UPD from imprinting defect. (yang2021genotype–phenotypecorrelationsin pages 2-4) - If methylation normal: proceed to UBE3A sequencing for intragenic pathogenic variants; if negative, consider alternative diagnoses. (yang2021genotype–phenotypecorrelationsin pages 2-4)

10.2 EEG as supportive diagnostic/biomarker tool

Characteristic EEG patterns include high-amplitude rhythmic delta activity and genotype-associated spectral differences; quantitative EEG (qEEG) provides objective measures for both diagnosis support and therapeutic monitoring. (frohlich2019electrophysiologicalphenotypein pages 1-3, martinez2023quantitativeeeganalysis pages 1-2)

10.3 Differential diagnosis

Chromosomal microarray can identify other microdeletion syndromes that can mimic AS when methylation and UBE3A testing are negative. (yang2021genotype–phenotypecorrelationsin pages 2-4)

11. Outcomes / prognosis

11.1 Mortality and survival

The retrieved evidence notes seizure complications as a potential cause of death but does not provide robust life expectancy or mortality-rate estimates. (roberts2024epigeneticsinrare pages 12-14)

11.2 Morbidity

Major morbidity drivers include severe intellectual disability, communication impairment, epilepsy, motor impairment, and sleep problems. (roberts2024epigeneticsinrare pages 12-14, cassater2021clinicalcharacterizationof pages 1-3)

12. Treatment

12.1 Current clinical management (standard of care)

Current care is primarily supportive and symptomatic, including seizure management and multidisciplinary developmental/rehabilitative services. (ma2023praderwilliandangelman pages 2-5)

12.2 Disease-modifying and advanced therapeutics (2023–2024 emphasis)

A) ASO-mediated paternal UBE3A unsilencing (targeting UBE3A-ATS)

Mechanism: suppress UBE3A-ATS to unsilence paternal UBE3A. (lee2023antisenseoligonucleotidetherapy pages 1-4, markati2021therapiesinpreclinical pages 5-6)

  • Clinical safety/early efficacy signal (GTX-102 / apazunersen): A gene-therapy overview paper summarizes an open-label intrathecal Phase 1/2 experience where five participants received cumulative 20–105.3 mg; “acute inflammatory polyradiculopathy causing leg weakness” occurred in two patients (clinical hold; recovery after discontinuation), while mean CGI-AS improvement was +2.4 at 4.5 months with improvements in behavioral/motor measures. (davidson2022genebasedtherapeuticsfor pages 4-5)

B) Small-molecule unsilencing of paternal UBE3A (2024)

A 2024 Nature Communications study identified (S)-PHA533533 as a small-molecule unsilencer.

Abstract-supported quotes: - “(S)-PHA533533 … significantly increase[s] paternal Ube3a mRNA and UBE3A protein levels while downregulating Ube3a-ATS” (vihma2024ube3aunsilencerfor pages 1-2) - “peripheral delivery of (S)-PHA533533 in AS model mice induces widespread neuronal UBE3A expression” (vihma2024ube3aunsilencerfor pages 1-2)

Visual evidence: immunofluorescent images and schematics of UBE3A imprinting/unsilencing are shown in the extracted figures. (vihma2024ube3aunsilencerfor media e5b0fdd9, vihma2024ube3aunsilencerfor media f576f803)

C) RNA-targeting CRISPR/Cas (Cas13) unsilencing (2023)

A 2023 Molecular Therapy paper reports that an AAV-delivered high-fidelity Cas13 system targeting Ube3a-ATS can restore paternal Ube3a in cortex/hippocampus for up to four months and improve motor function in AS mice. (li2023ahighfidelityrnatargeting pages 1-3)

D) Outcome measures / biomarkers for trials and real-world use

Quantitative EEG delta power is a leading noninvasive biomarker and can be modeled longitudinally to detect target engagement and treatment effects. (spencer2022longitudinaleegmodel pages 1-3)

12.3 Clinical trials (real-world implementation; key records)

Below are high-salience interventional programs with ClinicalTrials.gov records retrieved in this run (URLs embedded in NCT identifiers):

1) ION582 (Olezarsen-class ASO; Ionis) — HALOS - NCT05127226 (Phase 1–2a; Recruiting; planned n≈70); intrathecal bolus; primary outcome safety/tolerability; includes PK endpoints (Cmax, Tmax, t1/2, CSF concentration). (NCT05127226 chunk 1) - URL: https://clinicaltrials.gov/study/NCT05127226 (ClinicalTrials.gov; first posted year in record: 2021) (NCT05127226 chunk 1)

2) ION582 — REVEAL (Phase 3) - NCT number was retrieved by search but not fully extracted in text chunks in this evidence set; should be pulled directly from ClinicalTrials.gov (listed as Phase 3 recruiting in the tool output but not included as an evidence chunk here).

3) GTX-102 / apazunersen (Ultragenyx) - NCT04259281 (Phase 1/2; Completed; actual enrollment 74); multiple-dose escalation; intrathecal injection; primary outcomes are AE/SAE counts and severity up to Day 337; includes PK (Cmax). (NCT04259281 chunk 1) - URL: https://clinicaltrials.gov/study/NCT04259281 (record year: 2020) (NCT04259281 chunk 1) - NCT06617429 (Phase 3; Active not recruiting; actual enrollment 129); randomized, double-blind, sham-controlled; primary endpoint Bayley-4 cognitive raw score change at Day 338. (NCT06617429 chunk 1) - URL: https://clinicaltrials.gov/study/NCT06617429 (record year: 2024) (NCT06617429 chunk 1) - NCT06415344 (Phase 3 LTE; Enrolling by invitation; enrollment 255); open-label intrathecal flexible dosing; primary outcome AE/SAE frequency over 5 years. (NCT06415344 chunk 1) - URL: https://clinicaltrials.gov/study/NCT06415344 (record year: 2024) (NCT06415344 chunk 1) - NCT07157254 (Phase 2; Recruiting; enrollment 60); open-label basket study by genotype/age; includes Bayley-4 cognitive and a multidomain responder index (MDRI) endpoints. (NCT07157254 chunk 1) - URL: https://clinicaltrials.gov/study/NCT07157254 (record year: 2025) (NCT07157254 chunk 1)

Note: None of the retrieved ClinicalTrials.gov chunks included posted results modules; thus, efficacy should be treated as investigational pending peer-reviewed trial publications. (NCT05127226 chunk 1, NCT04259281 chunk 1, NCT06617429 chunk 1)

12.4 Suggested MAXO terms (examples)

  • Intrathecal drug administration: MAXO:0000934 (conceptual; verify exact MAXO ID in ontology browser)
  • Antisense oligonucleotide therapy: MAXO:000XXXX (needs MAXO lookup; not present in retrieved evidence)
  • Physical therapy / occupational therapy / speech therapy: MAXO terms not retrieved here; should be mapped from clinical guidelines.

13. Prevention

Primary prevention of de novo genetic events is not generally feasible; prevention focuses on: - Genetic counseling and molecular subtype determination to inform recurrence risk. (ma2023praderwilliandangelman pages 2-5) - Prenatal or preimplantation genetic testing may be applicable for families with known pathogenic UBE3A variants or imprinting center defects, but detailed guideline sources were not in the retrieved corpus.

14. Other species / natural disease

No naturally occurring veterinary AS analogs were identified in the retrieved evidence.

15. Model organisms

15.1 Mouse models

  • Maternal Ube3a knockout mice are widely used; specialized lines enable temporal reinstatement and drug screening using paternal-allele reporter systems. (santos2023stemcellmodels pages 2-4)

15.2 Rat models

  • A CRISPR-engineered rat with complete maternal Ube3a deletion shows age-dependent EEG delta power increases, epileptiform activity, and seizure phenotypes, supporting translational biomarker development. (born2021earlydevelopmentaleeg pages 1-2)

15.3 Nonhuman primate (rhesus macaque)

15.4 Human stem cell models (iPSC/ESC and organoids)

  • PSC-derived neurons and organoids recapitulate imprinting dynamics: UBE3A decreases while UBE3A-ATS increases during neuronal differentiation; models show electrophysiological immaturity and altered calcium transients/synaptic plasticity, supporting mechanism studies and drug screening. (santos2023stemcellmodels pages 10-11, santos2023stemcellmodels pages 9-10)

Data gaps and recommended next-step sources (for knowledge base completion)

Several requested fields (ICD-10/ICD-11 codes, MeSH ID, Orphanet ID, penetrance/life expectancy distributions, and MAXO IDs for specific interventions) were not present in the retrieved full-text evidence. For knowledge base completion, extract these from: OMIM (105830), Orphanet disease pages, MeSH browser, and ICD coding systems, and map ontologies via MONDO cross-references.

Key visual evidence (recent mechanism and unsilencing)

  • UBE3A imprinting schematic and paternal allele silencing by UBE3A-ATS in mature neurons (Vihma et al., 2024 figure crop). (vihma2024ube3aunsilencerfor media f576f803)
  • Immunofluorescent evidence of increased paternal UBE3A signal after (S)-PHA533533 treatment (Vihma et al., 2024 figure crop). (vihma2024ube3aunsilencerfor media e5b0fdd9)

References

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