Search Results (54)

Angelman syndrome (AS) is a neurodevelopmental disorder caused by the loss of maternal UBE3A expression, leading to disrupted proteostasis and synaptic dysfunction. Adenosine is a ubiquitous neuromodulator whose G protein-coupled receptors (ARs) regulate neuronal differentiation and neurite outgrowth during development. Here, we investigated AR signaling and their influence on survival–autophagy balance and neuronal morphology in an AS cellular model. Using SH-SY5Y cells with silenced UBE3A, we found that UBE3A loss markedly decreased A1AR, A2BAR, and A3AR protein levels while significantly increasing A2AR expression. Ligand affinity was preserved across genotypes, but A1AR and A2AAR desensitization kinetics were significantly slower in UBE3A-deficient cells. These effects were associated with reduced recruitment of G protein-coupled receptor kinase 2 (GRK2) to the plasma membrane and decreased GRK2–AR association in UBE3A-deficient cells, suggesting a possible contribution of altered GRK2 dynamics to prolonged AR signaling. Functionally, A1AR and A2AR agonists preferentially promoted survival of UBE3A-deficient cells and modulated the MDM2–p53 axis and autophagy markers; A1R stimulation also increased neurite density in UBE3A-deficient cells. Together, these results identify AR-level alterations and defective desensitization machinery in AS neuronal cells and link receptor changes to downstream proteostasis and morphological phenotypes relevant to AS pathophysiology. Full article

Background/Objectives: Angelman syndrome is a neurodevelopmental disorder resulting from a deficiency of the maternally inherited UBE3A gene. In mature neurons, UBE3A expression is restricted to the maternal allele due to tissue-specific genomic imprinting, while the paternal allele is silenced in cis by the UBE3A antisense transcript (UBE3A-ATS). To date, numerous strategies have been employed to activate paternal UBE3A expression. In this study, we utilized RNA interference (RNAi) to investigate the downregulation of UBE3A-ATS in mouse primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons. Methods: To induce paternal UBE3A expression, we employed small interfering RNA (siRNA) oligonucleotides (20 mouse candidates and 47 human candidates) and lentiviral short hairpin RNA (LV-shRNA) targeting SNORD115 to suppress UBE3A-ATS expression in both mouse primary neurons and iPSCs. Subsequently, we assessed the expression levels of Angelman syndrome-related neighboring and target genes at the transcript and, where applicable, protein levels. Results: Following treatment with siSnord115 or LV-shSnord115, we observed a reduction in Ube3a-ATS and a corresponding activation of paternal Ube3a RNA and protein expression in both Ube3a^P-YFP/m+ and Ube3a^p+/m− mouse primary neurons. A similar effect was observed upon treatment with LV-shSNORD115s in human iPSC-derived neurons. Conclusions: shRNA-mediated inhibition of Ube3a-ATS by targeting Snord115 effectively restores Ube3a/UBE3A expression in both mouse neurons and human iPSCs. While promising, the mild reduction in Snord116 raises concerns about potential off-target effects. AAV-based delivery of shRNA shows potential, but its translational applicability remains to be evaluated in vivo. Full article

Prader–Willi (PWS) and Angelman (AS) syndromes were the first examples in humans with errors in genomic imprinting, usually from de novo 15q11-q13 deletions of different parent origin (paternal in PWS and maternal in AS). Dozens of genes and transcripts are found in the 15q11-q13 region, and may play a role in PWS, specifically paternally expressed SNURF-SNRPN and MAGEL2 genes, while AS is due to the maternally expressed UBE3A gene. These three causative genes, including their encoding proteins, were targeted. This review article summarizes and illustrates the current understanding and cause of both PWS and AS using strategies to include the literature sources of key words and searchable web-based programs with databases for integrated gene and protein interactions, biological processes, and molecular mechanisms available for the two imprinting disorders. The SNURF-SNRPN gene is key in developing complex spliceosomal snRNP assemblies required for mRNA processing, cellular events, splicing, and binding required for detailed protein production and variation, neurodevelopment, immunodeficiency, and cell migration. The MAGEL2 gene is involved with the regulation of retrograde transport and promotion of endosomal assembly, oxytocin and reproduction, as well as circadian rhythm, transcriptional activity control, and appetite. The UBE3A gene encodes a key enzyme for the ubiquitin protein degradation system, apoptosis, tumor suppression, cell adhesion, and targeting proteins for degradation, autophagy, signaling pathways, and circadian rhythm. PWS is characterized early with infantile hypotonia, a poor suck, and failure to thrive with hypogenitalism/hypogonadism. Later, growth and other hormone deficiencies, developmental delays, and behavioral problems are noted with hyperphagia and morbid obesity, if not externally controlled. AS is characterized by seizures, lack of speech, severe learning disabilities, inappropriate laughter, and ataxia. This review captures the clinical presentation, natural history, causes with genetics, mechanisms, and description of established laboratory testing for genetic confirmation of each disorder. Three separate searchable web-based programs and databases that included information from the updated literature and other sources were used to identify and examine integrated genetic findings with predicted gene and protein interactions, molecular mechanisms and functions, biological processes, pathways, and gene-disease associations for candidate or causative genes per disorder. The natural history, review of pathophysiology, clinical presentation, genetics, and genetic-phenotypic findings were described along with computational biology, molecular mechanisms, genetic testing approaches, and status for each disorder, management and treatment options, clinical trial experiences, and future strategies. Conclusions and limitations were discussed to improve understanding, clinical care, genetics, diagnostic protocols, therapeutic agents, and genetic counseling for those with these genomic imprinting disorders. Full article

Background/Objectives: Cutaneous hypopigmentation is a common clinical sign observed in a variety of disorders. It may be congenital or acquired, localized or diffuse, and can range from benign to being associated with systemic conditions, including those affecting the central nervous system. Recognition of the key clinical features associated with each disorder is essential for accurate diagnosis and for differentiating one condition from another. Methods: PubMed, Embase, and Scopus databases were used to prepare a systematic review. Search terms were: “congenital”, “cutaneous”, “localized”, “diffuse”, “hypopigmentation” and “neurological disorders/signs”. The focus was on congenital cutaneous hypopigmentation, distinguishing between localized and diffuse presentations, with emphasis on neurological involvement. Peer-reviewed articles, case series, and original studies with neurological manifestations of the disease were reviewed. Cutaneous hypopigmentation disorders associated with diffuse cerebral involvement include syndromes such as Chediak–Higashi, Griscelli, Elejalde, Cross, Tietz albinism-deafness, Prader–Willi, Angelman, and several congenital metabolic disorders. In contrast, the ‘localized’ group comprises syndromes such as Waardenburg, Incontinentia pigmenti, and the phacomatoses, including hypomelanosis of Ito and tuberous sclerosis complex. Results: Overlapping phenotypes and genetic heterogeneity lead to diagnostic challenges and potential errors suggesting multiple specialists. The main clinical features of each disorder are discussed, with particular attention paid to neurological signs. A practical flowchart is provided to help distinguish between ‘diffuse’ and ‘localized’ forms with neurological involvement. Conclusions: Early identification of cutaneous features, followed by comprehensive clinical and instrumental evaluation, enables timely and accurate diagnosis, ultimately improving the clinical outcomes for affected children. Full article

Angelman Syndrome (AS) is a neurodevelopmental disorder caused by the deficiency of the UBE3A gene that for a E3 ligase protein part of the ubiquitin–proteasome system (UPS). Autophagy and UPS systems remove abnormal proteins, but any dysfunction in these processes can affect neuronal development and wellbeing. Herein, the involvement of the UPS/autophagy system in the regulation of intracellular signaling pathways related to toxic protein accumulation was investigated in cellular/mice AS models, silenced for UB3A (UB3A⁻). The main findings are as follows: (i) autophagy was upregulated in UBE3A⁻ cells with respect to control cells; (ii) a dysregulation of the AKT/mTOR pathway, linked to autophagy/synaptic development, was evidenced in cellular/animal models of AS with respect to controls; (iii) the ubiquitin ligase MDM2 was downregulated, and the tumor suppressor p53, normally inhibited by MDM2, enhanced its expression and transcriptional activity in UB3A⁻ cells with respect to controls. Finally, UB3A⁻ cells presented a significant alteration in the levels of β-amyloids with respect to control cells, and a reduction of α-synuclein levels, typical of neurodevelopmental disorder. Nevertheless, UB3A⁻ cells do not show evident morphological abnormalities. Overall, these data suggest that AS models presented an altered signaling pathway related to autophagy/UPS systems, potentially leading to the accumulation of toxic proteins affecting synaptic development. Full article

Assisted reproductive technologies (ARTs) have revolutionized infertility treatment, leading to the birth of over 10 million children worldwide. Despite their success, increasing concerns have been expressed regarding the potential long-term outcomes of ART-conceived individuals, particularly in relation to imprinting disorders (IDs). IDs result from the abnormal expression of imprinted genes, which are expressed in a parent-of-origin-specific manner and regulated by epigenetic mechanisms (e.g., DNA methylation). Disruption of these processes, through environmental, genetic, or procedural factors, can lead to disorders such as Beckwith–Wiedemann syndrome (BWS), Silver–Russell syndrome (SRS), Angelman syndrome (AS), and Prader–Willi syndrome (PWS). These syndromes are characterized by distinct clinical features, including growth abnormalities, neurodevelopmental delay, endocrine dysfunction, and cancer predisposition. ART procedures, especially ovarian hyperstimulation, in vitro fertilization (IVF), and embryo culture, coincide with critical periods of epigenetic reprogramming and may contribute to epimutations in imprinting control regions. In this review, we explored epidemiology, molecular mechanisms, and prenatal diagnostic strategies related to these four IDs in the context of ART. The findings suggest a higher prevalence of BWS and SRS in ART-conceived children. The data regarding AS and PWS are more controversial, with conflicting results across populations and methodologies. Although a causal link between ART and IDs remains debated, evidence suggests the potential contribution of ART procedures to epigenetic dysregulation in susceptible individuals. Further large-scale, methodologically rigorous studies will be essential to clarify this association and inform safer ART practices. Full article

Kleefstra syndrome (KS) is a rare neurodevelopmental disorder associated with disruptions in the EHMT1 gene, often leading to intellectual disability, autism spectrum behaviors and epilepsy. The electroencephalogram (EEG) serves as a non-invasive tool to explore brain function in KS; yet, systematic characterizations of EEG features remain extremely limited. This review synthesizes current evidence on EEG findings in KS, highlighting the high prevalence of nonspecific abnormalities and seizures, but the absence of a consistent electrophysiological biomarker. Given the growing role of machine learning (ML) in extracting patterns from EEG data in related disorders—such as Angelman, Rett and Fragile X syndromes—this review explores how similar approaches could be adapted for KS. Despite promising perspectives, a lack of large-scale, publicly available EEG datasets hinders the application of ML methodologies in KS research. Future directions are proposed to address these gaps, including standardized EEG data collection, adoption of quantitative EEG analyses and integration of ML techniques adapted for small datasets. This multidisciplinary strategy holds potential for improving early diagnosis, monitoring and personalized interventions in Kleefstra syndrome. Full article

Drug-resistant epilepsy (DRE) affects 20–30% of patients with epilepsy who fail to achieve seizure control with antiseizure medications, posing a significant therapeutic challenge. In this narrative review, we examine the clinical efficacy and safety of the classic ketogenic diet (cKD) and its variants, including the modified Atkins diet (MAD), medium-chain triglyceride diet (MCTD), and low glycemic index treatment (LGIT), in patients with genetically confirmed drug-resistant epilepsy. These diets induce a metabolic shift from glucose to ketones, enhance mitochondrial function, modulate neurotransmitter balance, and exert anti-inflammatory effects. However, genetic factors strongly influence the efficacy and safety of the cKD, with absolute indications including glucose transporter type 1 deficiency syndrome (GLUT1DS) and pyruvate dehydrogenase complex deficiency (PDCD). Preferred adjunctive applications of the KD include genetic epilepsies, such as SCN1A-related Dravet syndrome, TSC1/TSC2-related tuberous sclerosis complex, and UBE3A-related Angelman syndrome. However, because of the risk of metabolic decompensation, the cKD is contraindicated in patients with pathogenic variants of pyruvate carboxylase and SLC22A5. Recent advancements in precision medicine suggest that genetic and microbiome profiling may refine patient selection and optimize KD-based dietary interventions. Genome-wide association studies and multiomics approaches have identified key metabolic pathways influencing the response to the cKD, and these pave the way for individualized treatment strategies. Future research should integrate genomic, metabolomic, and microbiome data to develop biomarker-driven dietary protocols with improved efficacy and safety. As dietary therapies continue to evolve, a personalized medical approach is essential to maximize their clinical utility for genetic epilepsy and refractory epilepsy syndromes. Full article

The ubiquitin-protein ligase E3A (UBE3A, aka E6-AP), an E3 ligase belonging to the HECT family, plays crucial roles in the stability of various proteins through the proteasomal degradation system. Abnormal UBE3A activity is essential for the initiation and progression of several cancers. A gain of function and an overdosage of maternal UBE3A is associated with an increased risk of autism spectrum disorders. Conversely, a loss of function due to mutations, deletions, paternal duplications, or imprinting defects in neurons leads to Angelman syndrome. Emerging evidence suggests that abnormal UBE3A activity may also contribute to the development of various brain disorders, including schizophrenia, Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease, making UBE3A a protein of significant interest. However, research on UBE3A’s functions in the brain has primarily focused on neurons due to the imprinting of UBE3A in mature neuronal cells, while being obscured in glia. This review outlines the expression of UBE3A in neurons and glial cells based on published studies, highlights newly identified patterns of UBE3A, such as its secretion, and emphasizes the involvement of UBE3A in neurodegenerative diseases. Furthermore, we summarize glial UBE3A and propose a model of bi-directional interactions between the neurons and glia mediated by UBE3A that underlies brain functions. Insights gained from this research could provide new avenues for therapeutic interventions targeting various brain disorders. Full article

Background/Objectives: Recent research has focused on the study of the epigenetic role of nutrition as a tool which is expected to introduce new perspectives in the field of disease prevention and management. Although maternal nutrition is one of the best-studied mechanisms of epigenetic modifications of the fetus/newborn, less is known on the impact of childhood/adolescent nutrition on the regulation of epigenetic mecha-nisms after the first year of life. The aim of the present study was the assessment of the epigenetic role of nutrition in the health and development of children and adolescents. Methods: A systematic review was performed according to the Preferred Reported Items for Systematic Reviews and Meta-analyses guidelines in five databases (PubMed, Cochrane, Science Direct, Scopus, and Google Scholar) up to 31 October 2024, which yielded 17 eligible studies. The Newcastle–Ottawa Scale and the Cochrane Collabora-tion Risk of Bias-2 tool were used for the evaluation of risk of bias in observational studies and randomized trials, respectively. Results: Three studies investigated the epi-genetic modifications due to lifestyle interventions combining changes both in diet and physical activity; the remaining 14 studies examined the role of dietary nutrients in the regulation of epigenetic mechanisms in various health conditions, such as Angelman’s syndrome, parenteral nutrition in Intensive Care Units, attention deficit hyperactivity disorder, risk of cardiovascular diseases, asthma or food sensitization, obesity, insulin resistance, and type 2 diabetes or evaluated epigenetic markers as new tools for the comprehension and prediction of the participants’ response to nutritional interven-tions. Conclusions: The important impact of diet on the regulation of epigenetic mech-anisms and the expression of various genes and gene pathways could be utilized for personalized nutritional interventions in various pediatric health conditions. Full article

Background: Balanced chromosomal translocations occur in approximately 0.16 to 0.20% of live births. While most carriers are phenotypically normal, they are at risk of generating unbalanced gametes during meiosis, leading to genetic anomalies such as aneuploidies, deletions, duplications, and gene disruptions. These anomalies can result in spontaneous abortions or congenital anomalies, including neurodevelopmental disorders. Complex chromosomal rearrangements (CCRs) involving more than two chromosomes are rare but further increase the probability of producing unbalanced gametes. Neurodevelopmental disorders such as Angelman syndrome (AS) and duplication 15q11q13 syndrome (Dup15q) are associated with such chromosomal abnormalities. Methods: This study describes a family with a de novo maternal balanced double translocation involving chromosomes 13, 19, and 15, resulting in two offspring with unbalanced chromosomal abnormalities. Cytogenetic evaluations were performed using GTG banding, fluorescence in situ hybridization (FISH), and low-pass whole-genome sequencing (LP-WGS). Methylation analysis was conducted using methylation-sensitive high-resolution melting (MS-HRM) to diagnose Angelman syndrome. Results: The cytogenetic and molecular analyses identified an 8.9 Mb duplication in 15q11.2q13.3 in one child, and an 8.9 Mb deletion in the same region in the second child. Both abnormalities affected critical neurodevelopmental genes, such as SNRPN. FISH and MS-HRM confirmed the chromosomal imbalances and the diagnosis of Angelman syndrome in the second child. The maternal balanced translocation was found to be cryptic, contributing to the complex inheritance pattern. Conclusion: This case highlights the importance of using multiple genetic platforms to uncover complex chromosomal rearrangements and their impact on neurodevelopmental disorders. The findings underscore the need for thorough genetic counseling, especially in families with such rare chromosomal alterations, to manage reproductive outcomes and neurodevelopmental risks. Full article

The need for sleep is universal, and the ability to meet this need impacts the quality of life for patients, families, and caregivers. Although substantial progress has been made in treating rare diseases, many patients have unmet medical sleep needs, and current regulatory policy makes it prohibitively difficult to address those needs medically. This opinion reviews the rare disease experience with sleep disorders and explores potential solutions. First, we provide case profiles for the rare diseases Wilson’s Disease, Angelman Syndrome, and Prader–Willi Syndrome. These profiles highlight challenges in rare disease diagnosis and barriers to pinpointing disease pathophysiology, including biomarkers that intersect with sleep disorders. Second, we transition to a bird’s eye view of sleep disorders and rare diseases by reporting input from a stakeholder discussion with the U.S. Food and Drug Administration regarding abnormal sleep patterns in various rare diseases. Last, in response to the profound unmet medical needs of patients with rare diseases and sleep disorders, we propose adapting and using the clinical trial design known as a “basket trial”. In this case, a basket trial would include patients with different rare diseases but the same debilitating symptoms. This research approach has the potential to benefit many rare disease patients who are otherwise left with profound unmet medical needs. Full article

The 15q11.2q13 chromosomal region is particularly susceptible to chromosomal rearrangements due to low-copy repeats (LCRs) located inside this area. Specific breakpoints (BP1-BP5) that lead to deletions and duplications of variable size have been identified. Additionally, this specific region contains several imprinted genes, giving rise to complex syndromes (Prader–Willi, Angelman and 15q11-q13 duplication syndromes). 15q11.2-q13 duplication syndrome has been associated with neurodevelopmental disorders (hypotonia, developmental delay, speech delay and seizures) and ASD but is characterized by variable expressivity and reduced penetrance, features that make genetic counseling a complex procedure especially in prenatal cases. In the present study, a total of 14 pre- and postnatal cases were diagnosed as 15q11.2q13 duplication carriers using Affymetrix CytoScan 750 K array-CGH, and our analysis combined these with 120 cases existing in the literature. The inheritance pattern of the cases of this study is unknown, but as a review of the literature revealed, 62.96% of the affected carriers inherited the duplicated area from their mother. The combined results of this analysis (the present study and the literature) show that in the majority of the cases, the phenotype is a compound phenotype, with clinical characteristics that include ASD, intellectual disability, developmental delay and an absence of speech. The aim of this paper is to deliver new possibilities to genetic counseling that can be provided in prenatal and postnatal cases as the phenotype of 15q11.2q13 microduplication carriers cannot be fully predicted; so, clinical diagnoses should be a combination of molecular findings and clinical manifestations that are present. Full article

The formation of the human gut microbiome initiates in utero, and its maturation is established during the first 2–3 years of life. Numerous factors alter the composition of the gut microbiome and its functions, including mode of delivery, early onset of breastfeeding, exposure to antibiotics and chemicals, and maternal stress, among others. The gut microbiome–brain axis refers to the interconnection of biological networks that allow bidirectional communication between the gut microbiome and the brain, involving the nervous, endocrine, and immune systems. Evidence suggests that the gut microbiome and its metabolic byproducts are actively implicated in the regulation of the early brain development. Any disturbance during this stage may adversely affect brain functions, resulting in a variety of neurodevelopmental disorders (NDDs). In the present study, we reviewed recent evidence regarding the impact of the gut microbiome on early brain development, alongside its correlation with significant NDDs, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, Tourette syndrome, cerebral palsy, fetal alcohol spectrum disorders, and genetic NDDs (Rett, Down, Angelman, and Turner syndromes). Understanding changes in the gut microbiome in NDDs may provide new chances for their treatment in the future. Full article

Background: The Angelman Syndrome Registry (RISA) was developed as a retrospective study with the following objectives: to evaluate the clinical history of individuals with Angelman Syndrome (AS) in Italy and compare it with the existing literature; to investigate the feasibility of gathering data by directly involving participants in the data collection process; and to explore the relationship between different symptoms and genotypes. Methods: Established in 2018, RISA enrolled a total of 82 participants, with 62 (75.6%) providing complete data. Demographic, clinical, and genetic information was collected using electronic case report forms. Descriptive statistics characterized the sample, while associations between genotype and clinical characteristics were examined. Results: Descriptive analysis revealed a median participant age of 8.0 years, with males comprising 48.8% of the sample. Deletion (58.1%) was the most common genotype. The majority (82.2%) experienced epilepsy, with seizures typically onset before 3 years of age. Most patients (86.2%) required multiple anti-epileptic drugs for control, with generalized tonic–clonic seizures and atypical absence seizures being most prevalent. The deletion group exhibited more severe developmental delays and a trend towards higher seizure severity. Sleep problems affected 69.4% of participants, characterized by difficulties in sleep onset and maintenance. Conclusions: This study offers valuable insights into the clinical history and genetic characteristics of AS in Italy, consistent with the prior literature. Additionally, it underscores the efficacy of patient registries in capturing comprehensive data on rare diseases such as AS, highlighting their potential to advance research and enhance patient care. Full article