2026-08-17 | Sleep disruption and neuropsychiatric features in Angelman syndrome: insights into underlying neurobiology.
Sleep disorders are a core feature of Angelman syndrome (AS), affecting approximately 80% of individuals. They typically manifest as insomnia and disrupted sleep-wake cycles and contribute substantially to the burden experienced by affected individuals and their families. AS is caused by loss of function of the ubiquitin protein ligase E3A (UBE3A) gene, which encodes the E3 ubiquitin ligase E6AP, a protein essential for synaptic development and function. In individuals with a maternal 15q11-q13 deletion, concomitant deletion of neighboring non-imprinted genes, including GABRB3, GABRA5, GABRG3, ATP10A, and HERC2, may also contribute to the phenotype. Evidence from animal models further indicates that UBE3A plays a key role in sleep homeostasis and circadian rhythm regulation, including through interactions with core clock genes such as BMAL1. In this narrative review, we examine the role of UBE3A in sleep regulation and outline the principal sleep disturbances observed in AS, integrating findings from both preclinical models and human studies, while also considering genotype-phenotype correlations for the main clinical manifestations. The available evidence suggests that sleep disruption may be closely linked to the core neurological and behavioral features of AS, particularly epilepsy and behavioral abnormalities, through shared pathophysiological mechanisms related to UBE3A deficiency. Early identification and management of sleep disturbances may therefore represent a potentially modifiable factor for improving behavioral outcomes, seizure control, and overall quality of life in individuals with AS. In addition, sleep measures should be considered as potentially relevant clinical endpoints in ongoing trials of emerging therapeutic strategies.
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2026-07-31 | Comprehensive chemical and enantiomeric characterization of commercial turpentine oils by GC-MS.
Recent reports from families of individuals with Angelman syndrome (AS), a rare neurodevelopmental disorder characterised by severe neurological impairment and epilepsy, have described perceived neurological improvements following the topical application of a commercial turpentine oil (TO). These observations prompted the present analytical study, which aimed to characterise and quantify the terpenoid composition of 2 commercial TOs (Diamond and Creekwood), together with 6 additional commercial TOs, using gas chromatography-mass spectrometry (GC-MS). Analysis of 6 TOs reported to originate from Pinus pinaster revealed similar combined percentages of α- and β-pinene (≈75%), except for one oil that exhibited a more complex profile, a lower α-pinene content (≈30%), and the presence of eucalyptol, which is uncommon in TOs from this species. The Creekwood oil contained a higher proportion of α-pinene (≈76%) and a markedly lower β-pinene content (≈3%) than the Diamond oil (≈62% and ≈26%, respectively). Chiral GC-MS analysis further revealed contrasting enantiomeric distributions, with (-)-α-pinene predominating in the Diamond oil and (+)-α-pinene in the Creekwood oil, while (-)-β-pinene predominated in both samples. For quantitative analysis, the analytical method was successfully validated, demonstrating suitable detection (1.5-5.0 mg/L) and quantification (5.0-16.7 mg/L) limits, good linearity (r2>0.991), and acceptable precision and accuracy (<15%). These findings demonstrate substantial chemical variability among commercial TOs and provide a framework for future studies on the biological effects of pine resin terpenoids in neuronal models relevant to AS.
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2026-07-14 | Emerging Therapies for Angelman Syndrome.
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.
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2026-07-04 | The SNRPN Bipartite Imprinting Centre in Region 15q11–q13 and Its Epigenetic Role in the Pursuit of a Cure for Angelman Syndrome
Angelman syndrome is a severe neurodevelopmental disorder arising from functional loss of the maternal allele of UBE3A, a gene that sits within a cluster of imprinted loci on the long arm of chromosome 15. Expression across this region is governed by a bipartite imprinting centre associated with the SNRPN gene, made up of two physically separated but functionally interdependent elements: the Prader–Willi syndrome smallest region of deletion overlap and the Angelman syndrome smallest region of deletion overlap. Together these elements establish, in the germline, and maintain, throughout somatic life, the parent-of-origin-specific expression pattern that distinguishes Angelman syndrome from its reciprocal disorder, Prader–Willi syndrome. Because the paternal copy of UBE3A remains structurally intact in most patients with Angelman syndrome, merely silenced by a long non-coding antisense transcript whose own expression is dictated by the imprinting centre, this locus has become the focal point of an unusually concentrated translational effort: rather than replacing a missing gene, contemporary therapeutic strategies aim to reverse an epigenetic mark and thereby unmask a dormant but functional allele. This review draws together the structural biology of the bipartite imprinting centre, the molecular events that establish and maintain its parent-specific epigenotype, the diagnostic and clinical consequences of its disruption, and the rapidly maturing pipeline of antisense oligonucleotides, small molecules, and genome- or epigenome-editing tools designed to exploit this biology therapeutically. Recent clinical trial data, including electroencephalographic and behavioural endpoints from antisense oligonucleotide programmes, are critically appraised alongside preclinical work on CRISPR-based epigenetic editing of the imprinting centre itself, an approach with the conceptual elegance of intervening at the very switch that imprinting biology depends upon. The review concludes that while no disease-modifying therapy is yet approved, the convergence of detailed mechanistic understanding of the SNRPN bipartite imprinting centre with scalable epigenetic editing technologies represents the most plausible route towards a transformative, rather than purely symptomatic, treatment for Angelman syndrome, while candidly addressing the developmental, safety and translational obstacles that remain.
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2026-07-01 | Pseudohypoaldosteronism associated with mitochondrial dysfunction in Angelman syndrome
Pseudohypoaldosteronism (PHA) is an uncommon cause of hyperkalemic metabolic acidosis in infancy, typically secondary to structural, infectious, or genetic etiologies. Because renal tubular transport is adenosine triphosphate dependent, mitochondrial dysfunction may also produce a PHA-like phenotype. We report a 14-month-old girl with hyperkalemic metabolic acidosis and growth failure. Laboratory evaluation showed hyperkalemic metabolic acidosis with markedly elevated renin and aldosterone, consistent with a PHA-like phenotype. Bicarbonate and potassium-binding treatment provided suboptimal control. Organic acid abnormalities and an elevated lactate-to-pyruvate ratio raised suspicion of mitochondrial dysfunction, and vitamin supplementation (vitamin B, vitamin C, biotin, L-carnitine, and idebenone) promptly normalized acid-base status and potassium. Continued oral vitamin supplementation was associated with catch-up growth and allowed gradual tapering and eventual discontinuation of bicarbonate and potassium-binding agent at 1.8 and 3.4 years, respectively. The oxygen consumption rate in the fibroblasts was markedly reduced in galactose medium. For genetic analyses, targeted PHA/renal tubular acidosis-related gene panel testing, mitochondrial DNA sequencing and exome sequencing identified no pathogenic variants, whereas chromosomal microarray analysis identified a 5.76 Mb deletion in 15q (arr[hg19] 15q11.2q13.1(22,765,628-28,525,460) × 1), establishing the diagnosis of Angelman syndrome. This case links a PHA-like presentation, growth failure, and mitochondrial dysfunction to Angelman syndrome, supporting bioenergetic failure as a potentially treatable mechanism for refractory PHA.
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