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Frontiers in Behavioral Neuroscience 2023
PubMed: 37304763
DOI: 10.3389/fnbeh.2023.1201044 -
Science (New York, N.Y.) Dec 2019Disruptions in the ubiquitin protein ligase E3A () gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity...
Disruptions in the ubiquitin protein ligase E3A () gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases.
Topics: Angelman Syndrome; Animals; Calcium Channels, N-Type; Epilepsy; Humans; Mice; Models, Neurological; Neurons; Organoids; Potassium Channel Blockers; Seizures; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 31857479
DOI: 10.1126/science.aav5386 -
Journal of Neurodevelopmental Disorders Jun 2024Angelman syndrome (AS) is a neurodevelopmental disorder associated with severe global developmental delay. However, the ages at which different developmental skills are...
BACKGROUND
Angelman syndrome (AS) is a neurodevelopmental disorder associated with severe global developmental delay. However, the ages at which different developmental skills are achieved in these individuals remain unclear. We seek to determine the probability and the age of acquisition of specific developmental milestones and daily living skills in individuals with AS across the different molecular subtypes, viz. class I deletion, class II deletion, uniparental disomy, imprinting defect, and UBE3A variants.
METHODS
Caregivers participating in a longitudinal multicenter Angelman Syndrome Natural History Study completed a questionnaire regarding the age at which their children achieved specific developmental milestones and daily living skills. The Cox Proportional Hazard model was applied to analyze differences in the probability of achievement of skills at various ages among five molecular subtypes of AS.
RESULTS
Almost all individuals, regardless of molecular subtype, were able to walk with support by five years of age. By age 15, those with a deletion had at least a 50% probability of acquiring 17 out of 30 skills compared to 25 out of 30 skills among those without a deletion. Overall, fine and gross motor skills such as holding and reaching for small objects, sitting, and walking with support were achieved within a fairly narrow range of ages, while toileting, feeding, and hygiene skills tend to have greater variability in the ages at which these skills were achieved. Those without a deletion had a higher probability (25-92%) of achieving daily living skills such as independently toileting and dressing compared to those with a deletion (0-13%). Across all molecular subtypes, there was a low probability of achieving independence in bathing and brushing teeth.
CONCLUSION
Individuals with AS without a deletion are more likely to achieve developmental milestones and daily living skills at an earlier age than those with a deletion. Many individuals with AS are unable to achieve daily living skills necessary for independent self-care.
Topics: Humans; Angelman Syndrome; Activities of Daily Living; Female; Child, Preschool; Male; Child; Adolescent; Infant; Child Development; Longitudinal Studies; Motor Skills; Developmental Disabilities; Adult; Young Adult
PubMed: 38879552
DOI: 10.1186/s11689-024-09548-7 -
Therapeutic Advances in Rare Disease 2024Angelman syndrome (AS) and duplication 15q (dup15q) syndrome are rare neurogenetic conditions arising from a common locus on the long arm of chromosome 15. Individuals... (Review)
Review
Linking Angelman and dup15q data for expanded research (LADDER) database: a model for advancing research, clinical guidance, and therapeutic development for rare conditions.
Angelman syndrome (AS) and duplication 15q (dup15q) syndrome are rare neurogenetic conditions arising from a common locus on the long arm of chromosome 15. Individuals with both conditions share some clinical features (e.g. intellectual disability, epilepsy) and often require lifelong care. Disease-modifying therapies for both conditions are emerging, resulting in a significant need for a better understanding of the natural history of both AS and dup15q. Patient advocacy groups for both conditions recognized a need for a data repository that would link data on individuals from multiple sources to expand research, increase understanding of natural history, and accelerate the development of treatments, resulting in the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database. This paper describes the development and functionality of the LADDER Database - including challenges, lessons learned, and preliminary feasibility - and how it can be used as a model for other rare conditions.
PubMed: 38808315
DOI: 10.1177/26330040241254122 -
Annual Review of Pharmacology and... Jan 2021The genetic basis for most inherited neurodegenerative diseases has been identified, yet there are limited disease-modifying therapies for these patients. A new class of... (Review)
Review
The genetic basis for most inherited neurodegenerative diseases has been identified, yet there are limited disease-modifying therapies for these patients. A new class of drugs-antisense oligonucleotides (ASOs)-show promise as a therapeutic platform for treating neurological diseases. ASOs are designed to bind to the RNAs either by promoting degradation of the targeted RNA or by elevating expression by RNA splicing. Intrathecal injection into the cerebral spinal fluid results in broad distribution of antisense drugs and long-term effects. Approval of nusinersen in 2016 demonstrated that effective treatments for neurodegenerative diseases can be identified and that treatments not only slow disease progression but also improve some symptoms. Antisense drugs are currently in development for amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, and Angelman syndrome, and several drugs are in late-stage research for additional neurological diseases. This review highlights the advances in antisense technology as potential treatments for neurological diseases.
Topics: Humans; Neurodegenerative Diseases; Oligonucleotides, Antisense; Parkinson Disease; Pharmaceutical Preparations; RNA
PubMed: 33035446
DOI: 10.1146/annurev-pharmtox-010919-023738 -
Neurotherapeutics : the Journal of the... Jul 2021Angelman syndrome (AS) is a rare (~1:15,000) neurodevelopmental disorder characterized by severe developmental delay and intellectual disability, impaired communication... (Review)
Review
Angelman syndrome (AS) is a rare (~1:15,000) neurodevelopmental disorder characterized by severe developmental delay and intellectual disability, impaired communication skills, and a high prevalence of seizures, sleep disturbances, ataxia, motor deficits, and microcephaly. AS is caused by loss-of-function of the maternally inherited UBE3A gene. UBE3A is located on chromosome 15q11-13 and is biallelically expressed throughout the body but only maternally expressed in the brain due to an RNA antisense transcript that silences the paternal copy. There is currently no cure for AS, but advancements in small molecule drugs and gene therapies offer a promising approach for the treatment of the disorder. Here, we review AS and how loss-of-function of the maternal UBE3A contributes to the disorder. We also discuss the strengths and limitations of current animal models of AS. Furthermore, we examine potential small molecule drug and gene therapies for the treatment of AS and associated challenges faced by the therapeutic design. Finally, gene therapy offers the opportunity for precision medicine in AS and advancements in the treatment of this disorder can serve as a foundation for other single-gene neurodevelopmental disorders.
Topics: Angelman Syndrome; Animals; Anticonvulsants; Biological Products; Genetic Therapy; Humans; Isoxazoles; Neurodevelopmental Disorders; RNA, Antisense; Recombinant Fusion Proteins; Ubiquitin-Protein Ligases
PubMed: 34528170
DOI: 10.1007/s13311-021-01082-x -
Nature Nov 2020Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a mutation or deletion of the maternally inherited UBE3A allele. In neurons, the paternally...
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a mutation or deletion of the maternally inherited UBE3A allele. In neurons, the paternally inherited UBE3A allele is silenced in cis by a long non-coding RNA called UBE3A-ATS. Here, as part of a systematic screen, we found that Cas9 can be used to activate ('unsilence') paternal Ube3a in cultured mouse and human neurons when targeted to Snord115 genes, which are small nucleolar RNAs that are clustered in the 3' region of Ube3a-ATS. A short Cas9 variant and guide RNA that target about 75 Snord115 genes were packaged into an adeno-associated virus and administered to a mouse model of AS during the embryonic and early postnatal stages, when the therapeutic benefit of restoring Ube3a is predicted to be greatest. This early treatment unsilenced paternal Ube3a throughout the brain for at least 17 months and rescued anatomical and behavioural phenotypes in AS mice. Genomic integration of the adeno-associated virus vector into Cas9 target sites caused premature termination of Ube3a-ATS at the vector-derived polyA cassette, or when integrated in the reverse orientation, by transcriptional collision with the vector-derived Cas9 transcript. Our study shows that targeted genomic integration of a gene therapy vector can restore the function of paternally inherited UBE3A throughout life, providing a path towards a disease-modifying treatment for a syndromic neurodevelopmental disorder.
Topics: Angelman Syndrome; Animals; CRISPR-Associated Protein 9; CRISPR-Cas Systems; Dependovirus; Disease Models, Animal; Female; Gene Editing; Gene Silencing; Genetic Therapy; Genetic Vectors; Humans; Male; Mice; Mice, Inbred C57BL; Nervous System; Paternal Inheritance; Phenotype; RNA, Long Noncoding; Ubiquitin-Protein Ligases
PubMed: 33087932
DOI: 10.1038/s41586-020-2835-2 -
Journal of Clinical Medicine Sep 2023Angelman Syndrome (AS) is a rare genetic disorder caused by lack of maternal UBE3A protein due to a deletion of the chromosome 15q11.2-q13 region, uniparental paternal...
Angelman Syndrome (AS) is a rare genetic disorder caused by lack of maternal UBE3A protein due to a deletion of the chromosome 15q11.2-q13 region, uniparental paternal disomy, imprinting center defect, or pathogenic variant in the gene. Characteristics are developmental delay, epilepsy, behavioral, and sleep problems. There is some evidence for hyperphagia, shorter stature, and higher BMI compared to neurotypical children, but longitudinal studies on growth are lacking. In this study, we analyzed prospectively collected data of 145 children with AS, who visited the ENCORE Expertise Center between 2010 and 2021, with a total of 853 visits. Children showed an elevated mean score of 25 on the Dykens Hyperphagia questionnaire (range 11-55) without genotype association. Higher scores were significantly associated with higher body mass index (BMI) standard deviation scores (SDS) ( = 0.004). Mean height was -1.2 SDS (SD 1.3), mean BMI-SDS was 0.6 (SD 1.7); 43% had a BMI-SDS > 1 and 20% had a BMI-SDS > 2. Higher BMI-SDS was significantly associated with non-deletion genotype ( = 0.037) and walking independently ( = 0.023). Height SDS decreased significantly with age ( < 0.001) and BMI-SDS increased significantly with age ( < 0.001. Onset of puberty was normal. In conclusion, children with AS showed moderate hyperphagia, lower height SDS, and higher BMI-SDS compared to norm data, with increasing deviation from the norm with age. It is uncertain how loss of maternal UBE3A function may influence growth. Attention to diet, exercise, and hyperphagia from an early age is recommended to prevent obesity and associated health problems.
PubMed: 37762921
DOI: 10.3390/jcm12185981 -
Pathophysiology : the Official Journal... Aug 2022Pain and nociception are different phenomena. Nociception is the result of complex activity in sensory pathways. On the other hand, pain is the effect of interactions... (Review)
Review
Pain and nociception are different phenomena. Nociception is the result of complex activity in sensory pathways. On the other hand, pain is the effect of interactions between nociceptive processes, and cognition, emotions, as well as the social context of the individual. Alterations in the nociceptive route can have different genesis and affect the entire sensorial process. Genetic problems in nociception, clinically characterized by reduced or absent pain sensitivity, compose an important chapter within pain medicine. This chapter encompasses a wide range of very rare diseases. Several genes have been identified. These genes encode the Nav channels 1.7 and 1.9 (, and genes, respectively), and its receptor tyrosine receptor kinase A, as well as the transcription factor PRDM12, and autophagy controllers (). Monogenic disorders provoke hereditary sensory and autonomic neuropathies. Their clinical pictures are extremely variable, and a precise classification has yet to be established. Additionally, pain insensitivity is described in diverse numerical and structural chromosomal abnormalities, such as Angelman syndrome, Prader Willy syndrome, Chromosome 15q duplication syndrome, and Chromosome 4 interstitial deletion. Studying these conditions could be a practical strategy to better understand the mechanisms of nociception and investigate potential therapeutic targets against pain.
PubMed: 35997391
DOI: 10.3390/pathophysiology29030035 -
AJNR. American Journal of Neuroradiology May 2020This work investigated alterations in functional connectivity (FC) and associated structures in patients with Angelman syndrome (AS) by using integrated quantitative...
BACKGROUND AND PURPOSE
This work investigated alterations in functional connectivity (FC) and associated structures in patients with Angelman syndrome (AS) by using integrated quantitative imaging analysis and connectivity measures.
MATERIALS AND METHODS
We obtained 3T brain MR imaging, including resting-state functional MR imaging, diffusion tensor imaging, and 3D T1-weighted imaging from children with AS ( = 14) and age- and sex-matched controls ( = 28). The brains of patients with AS were analyzed by measuring FC, white matter microstructural analysis, cortical thickness, and brain volumes; these were compared with brains of controls.
RESULTS
Interregional FC analysis revealed significantly reduced intra- and interhemispheric FC, especially in the basal ganglia and thalamus, in patients with AS. Significant reductions in fractional anisotropy were found in the corpus callosum, cingulum, posterior limb of the internal capsules, and arcuate fasciculus in patients with AS. Quantitative structural analysis also showed gray matter volume loss of the basal ganglia and diffuse WM volume reduction in AS compared with the control group.
CONCLUSIONS
This integrated quantitative MR imaging analysis demonstrated poor functional and structural connectivity, as well as brain volume reduction, in children with AS, which may explain the motor and language dysfunction observed in this well-characterized neurobehavioral phenotype.
Topics: Adolescent; Angelman Syndrome; Brain; Child; Child, Preschool; Diffusion Tensor Imaging; Female; Humans; Image Interpretation, Computer-Assisted; Male; Nerve Net; Neuroimaging
PubMed: 32381544
DOI: 10.3174/ajnr.A6531