アンジェルマン症候群

Angelman syndrome (OMIM #105830) is a rare neurodevelopmental disorder caused by loss of function of the maternally inherited UBE3A gene within the imprinted 15q11.2-q13 region. Although its clinical and molecular characteristics have been well described in European and Asian populations, data from low- and middle-income countries remain scarce. This retrospective study aimed to characterize the clinical and molecular features of Angelman syndrome in a Moroccan cohort and investigate genotype-phenotype correlations. Twenty-six patients with molecularly confirmed Angelman syndrome diagnosed between 2018 and 2022 at the Department of Medical Genetics, Hassan II University Hospital, Fez, were included. Molecular diagnosis was established using methylation-specific PCR, fluorescence in situ hybridization, and UBE3A sequencing. The cohort showed a female predominance (61.5%) and a median age at diagnosis of 5.7 years, indicating delayed diagnosis. Core clinical features included intellectual disability (100%), absent speech (96%), seizures (87%), Angelman syndrome-specific EEG abnormalities (87%), ataxia (87%), and hypersalivation (92%). Molecular analyses identified 15q11.2-q13 deletions in 77% of patients, imprinting defects or uniparental disomy in 11.5%, and UBE3A variants in 11.5%. Patients with maternal deletions exhibited a more severe neurological phenotype. This study, the largest Moroccan cohort of Angelman syndrome, highlights delayed diagnosis and limited access to molecular testing. Although hypersalivation was frequently observed, this finding should be interpreted cautiously, as it may reflect severe oromotor dysfunction and impaired swallowing rather than increased salivary secretion. These findings support earlier recognition, comprehensive molecular diagnosis, and improved access to genetic services in resource-limited settings. Clinical trial number: Not applicable.

UBE3A is a dosage-sensitive HECT E3 ubiquitin ligase whose neuronal expression is shaped by genomic imprinting at the 15q11.2-q13 locus. Opposite directions of UBE3A dosage imbalance contribute to distinct neurodevelopmental phenotypes: loss of maternal UBE3A underlies Angelman syndrome, whereas maternally derived 15q11.2-q13 copy-number gains, including interstitial duplications and isodicentric inv. dup(15)/idic(15) rearrangements, contribute to Dup15q-associated syndromic autism phenotypes. This review synthesizes evidence across molecular architecture, isoform biology, neuronal imprinting, synaptic regulation, circuit excitability, and therapeutic development. The central argument is that UBE3A should not be interpreted as a general explanation for autism, but as a mechanistically informative model for a defined subset of neurodevelopmental disorders in which parent-of-origin effects and copy-number state are central. In Angelman syndrome, UBE3A loss disrupts proteostasis, synaptic plasticity, inhibitory circuit function, and neuronal excitability through distributed rather than single-pathway mechanisms. In the maternally derived Dup15q spectrum, increased UBE3A dosage is strongly implicated in neuronal and synaptic abnormalities, although interval-wide dosage effects also contribute. Therapeutically, the direction of dosage change creates opposite translational requirements: restoration or paternal reactivation in Angelman syndrome versus dosage normalization in Dup15q-associated overdosage states. A dosage-directionality framework may therefore clarify how UBE3A biology connects molecular mechanism, developmental timing, and precision therapeutic design.

Angelman syndrome (AS) is a complex neurogenetic disorder characterized by severe global developmental delay, motor dysfunction, and epilepsy, primarily resulting from the lack of functional ubiquitin protein ligase E3A (UBE3A) protein expression in neurons. While current management remains largely symptomatic, the therapeutic landscape for AS is rapidly evolving. Emerging strategies aim to restore UBE3A function through upstream interventions, such as gene replacement therapy or unsilencing of the imprinted paternal allele, which is present but transcriptionally silenced in neurons due to genomic imprinting. This imprinting is mediated by the distal portion of a long non-coding RNA known as the UBE3A-antisense transcript (UBE3A-ATS). This UBE3A-ATS has become a key therapeutic target, with several approaches developed to unsilence the paternal allele, including antisense oligonucleotides (ASOs), CRISPR-based editing, synthetic microRNA, and other modalities. To date, three ASO programs have demonstrated promising signals in early clinical development, with reported improvements in clinical outcomes and electroencephalography (EEG) biomarkers. Given the potential for improved outcomes with early intervention, the inclusion of AS in broader genomic newborn screening programs is currently being explored. An early-intervention approach, or combination of approaches, holds significant promise for transforming the lives of individuals affected by AS with outcomes dependent on their age or genotype.

The 15q11.2 microdeletion is a chromosomal condition associated with a broad epileptic phenotype. It is differentiated from Angelman syndrome, which is typically a larger maternal deletion in an overlapping area. We describe a patient with a 15q11.2 microdeletion that has clinical and EEG biomarker features similar to those seen in Angelman syndrome. The patient was found to have a maternally inherited, likely pathogenic 258 kb deletion at 15q11.2. Novel electroclinical features associated with this finding included myoclonic absence seizures and other EEG findings consistent with the syndrome of Epilepsy with Myoclonic absences. The 15q11.2 microdeletion syndrome has a broad phenotype, and accuracy of diagnosis appears variable and inconsistent. EEG and knowledge of unique biomarkers may be a tool that can further refine genetic diagnosis.