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Journal of Neuroscience Research Jun 2020Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe mental retardation, absence of speech, abnormal motor coordination, abnormal EEG,... (Review)
Review
Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe mental retardation, absence of speech, abnormal motor coordination, abnormal EEG, and spontaneous seizure. AS is caused by a deficiency in the ubiquitin ligase E3A (Ube3a) gene product, known to play a dual role as both ubiquitin ligase and transcription coactivator. In AS animal models, multiple Ube3a substrates are accumulated in neurons. So far, studies in mouse models have either aimed at re-expressing Ube3a or manipulating downstream signaling pathways. Reintroducing Ube3a in AS mice showed promising results but may have two caveats. First, it may cause an overdosage in the Ube3a expression, which in turn is known to contribute to autism spectrum disorders. Second, in mutation cases, the exogenous Ube3a may have to compete with the mutated endogenous form. Such two caveats left spaces for developing therapies or interventions directed to targets downstream Ube3a. Notably, Ube3a expression is dynamically regulated by neuronal activity and plays a crucial role in synaptic plasticity. The abnormal synaptic plasticity uncovered in AS mice has been frequently rescued, but circuits symptoms like seizure are resistant to treatment. Future investigations are needed to further clarify the function (s) of Ube3a during development. Here I reviewed the recently identified major Ube3a substrates and signaling pathways involved in AS pathology, the Ube3a expression, imprinting and evolution, the AS mouse models that have been generated and inspired therapeutic potentials, and finally proposed some future explorations to better understand the AS pathology.
Topics: Angelman Syndrome; Animals; Disease Models, Animal; Mice; Neuronal Plasticity; Neurons; Ubiquitin-Protein Ligases
PubMed: 31867793
DOI: 10.1002/jnr.24576 -
Frontiers in Genetics 2021Establishing or ruling out a molecular diagnosis of Prader-Willi or Angelman syndrome (PWS/AS) presents unique challenges due to the variety of different genetic...
Establishing or ruling out a molecular diagnosis of Prader-Willi or Angelman syndrome (PWS/AS) presents unique challenges due to the variety of different genetic alterations that can lead to these conditions. Point mutations, copy number changes, uniparental isodisomy (i-UPD) 15 of two subclasses (segmental or total isodisomy), uniparental heterodisomy (h-UPD), and defects in the chromosome 15 imprinting center can all cause PWS/AS. Here, we outline a combined approach using whole-exome sequencing (WES) and DNA methylation data with methylation-sensitive multiplex ligation-dependent probe amplification (MLPA) to establish both the disease diagnosis and the mechanism of disease with high sensitivity using current standard of care technology and improved efficiency compared to serial methods. The authors encourage the use of this approach in the clinical setting to confirm and establish the diagnosis and genetic defect which may account for the secondary genetic conditions that may be seen in those with isodisomy 15, impacting surveillance and counseling with more accurate recurrence risks. Other similarly affected individuals due to other gene disorders or cytogenetic anomalies such as Rett syndrome or microdeletions would also be identified with this streamlined approach.
PubMed: 34046054
DOI: 10.3389/fgene.2021.608889 -
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 -
Hormone Research in Paediatrics Oct 2023Objectives - Angelman syndrome (AS) is a rare, genetic, neurodevelopmental disorder characterized by severe impairments in speech, cognition and motor skills accompanied...
Objectives - Angelman syndrome (AS) is a rare, genetic, neurodevelopmental disorder characterized by severe impairments in speech, cognition and motor skills accompanied by unique behaviors, distinct facial features and high prevalence of epilepsy and sleep problems. Despite some reports of short stature among AS patients, this feature is not included in the clinical criteria defined in 2005. We investigated growth patterns among AS patients with respect to mutation type, growth periods, family history and endocrine abnormalities. Methods - Data was collected from patients' medical files in AS national clinic. Mutation subtypes were divided to deletion and non-deletion. Four growth periods were defined: preschool, childhood, peak-height velocity, and final-height. Results - The cohort included 88 individuals (46 males), with 54 (61.4%) carrying deletion subtype. A median of 3 observations per individual , produced 280 data points. Final-height-SDS was significantly lower compared to general population (-1.23±1.26, p<0.001), and in deletion group vs. non-deletion (-1.67±1.3 vs. -0.65±0.96, p=0.03). Final-height-SDS was significantly lower compared to height-SDS in preschool period (-1.32 vs -0.47, p=0.007). Patient's final-height-SDS was significantly lower than the parents' (∆final-height-SDS=0.94±0.99, p=0.002). IGF1-SDS was significantly decreased compared to general population (-0.55±1.61, p=0.04), with lower values among deletion group (-0.70±1.44, p=0.01) Conclusions - AS patients demonstrate specific growth pattern with deceleration during childhood and adolescence resulting in significantly decreased final height compared to normal population, and even lower among deletion subgroup, which could be attributed to reduced IGF1 levels. We propose adding short stature to the clinical criteria and developing adjusted growth curves for AS population.
PubMed: 37844556
DOI: 10.1159/000534612 -
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 -
Frontiers in Psychiatry 2022This study investigated the mental development of children with Angelman syndrome (AS) in China and evaluated the relationship between neurodevelopment and molecular...
OBJECTIVE
This study investigated the mental development of children with Angelman syndrome (AS) in China and evaluated the relationship between neurodevelopment and molecular subtype, age, epilepsy, and sex using the Chinese version of the Griffith Mental Development Scale (GMDS-C) to provide detailed baseline data regarding neurodevelopment with AS in China.
METHODS
Participants were recruited from the AS Natural History Study. The GMDS-C was used to evaluate all participants' mental age and developmental quotients. The general quotient (GQ) and quotients of five subscales (sports, personal-social, auditory language, eye-hand coordination, and comprehensive performance) were calculated.
RESULTS
A total of 119 children (average age: 42.12 months; range, 7.5-95.5 months) with a genetic diagnosis of AS were enrolled. The median GQ score of the GMDS was 29.6 points (95% confidence interval, 28.6-33.25). The children had relatively good locomotor and personal-social skills but poor language skills. Overall, 89% (106/119) had mental ages younger than 24 months for all five subscales. The non-deletion group (i.e., without deletion in chromosome 15q11-13) had higher GQs and locomotor, personal-social, and performance subscale quotients. The GQ was significantly different among the three age subgroups and significantly correlated with age. Compared with the non-epilepsy group, the epilepsy group had lower GQs and lower quotients for the locomotor, personal-social, speech, language, and eye-hand coordination subscales.
CONCLUSION
Children with AS in China experience severe neurodevelopmental deterioration. In addition to age, molecular subtypes and the onset of seizures may also correlate with these patients' intellectual development. The GMDS-C is an accurate tool that can assess the clinical characteristics of AS. The data of this study can be used as baseline data for clinical trials performed to evaluate drug development or other AS treatment development.
PubMed: 35573374
DOI: 10.3389/fpsyt.2022.886028 -
The Clinical Neuropsychologist Jul 2022Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by core deficits in social communication and restricted and repetitive behaviors... (Review)
Review
OBJECTIVE
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by core deficits in social communication and restricted and repetitive behaviors and interests. Recent advances in clinical genetics have improved our understanding of genetic syndromes associated with ASD, which has helped clarify distinct etiologies of ASD and document syndrome-specific profiles of neurocognitive strengths and weaknesses. Pediatric neuropsychologists have the potential to be impactful members of the care team for children with genetic syndromes and their families.
METHOD
We provide a critical review of the current literature related to the neuropsychological profiles of children with four genetic syndromes associated with ASD, including Tuberous Sclerosis Complex (TSC), fragile X syndrome (FXS), 22q11.2 deletion syndrome, and Angelman syndrome. Recommendations for assessment, intervention, and future directions are provided.
RESULTS
There is vast heterogeneity in terms of the cognitive, language, and developmental abilities of these populations. The within- and across-syndrome variability characteristic of genetic syndromes should be carefully considered during clinical evaluations, including possible measurement limitations, presence of intellectual disability, and important qualitative differences in the ASD-phenotypes across groups.
CONCLUSIONS
Individuals with genetic disorders pose challenging diagnostic and assessment questions. Pediatric neuropsychologists with expertise in neurodevelopmental processes are well suited to address these questions and identify profiles of neurocognitive strengths and weaknesses, tailor individualized recommendations, and provide diagnostic clarification.
Topics: Autism Spectrum Disorder; Child; Fragile X Syndrome; Humans; Intellectual Disability; Neuropsychological Tests; Phenotype
PubMed: 34569897
DOI: 10.1080/13854046.2021.1980111 -
Quality of Life Research : An... Jul 2023The primary goal of this analysis is to describe the health-related quality of life (HRQoL), medical history, and medication use among adolescents and adults individuals... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The primary goal of this analysis is to describe the health-related quality of life (HRQoL), medical history, and medication use among adolescents and adults individuals with Angelman syndrome (AS).
METHODS
The analysis uses baseline data collected during the STARS study, a double-blind placebo controlled trial of gaboxadol (OV101) in adolescents and adults with AS. The HRQoL was estimated using EuroQoL 5-Dimension 5-Level (EQ-5D) health questionnaire proxy 1 version, which was completed by the caregivers. EQ-5D consists of two parts, a 5-dimension descriptive and a visual analogue scale (VAS) component. The utility score derived from EQ-5D ranges from 0 to 1 (perfect health) and VAS ranges from 0 to 100 (perfect health).
RESULTS
87 individuals with AS were included in the present analysis. The mean utility score was 0.44 ± 0.20 and VAS score was 84 ± 1.5. The EQ-5D data indicated that the self-care, mobility and daily activities were most impacted. All adolescents (100%) and most adults (93%) had at least moderate problems with self-care activities, such as washing or dressing themselves. More than half (55%) of the adolescents and adults had at least moderate issues with mobility and usual activities. Approximately, 30% of adolescents and adults had moderate to extreme problems with anxiety/depression. High baseline concomitant use of medications was observed across both age groups with an average of 5 medications being used per person.
CONCLUSION
This study highlights the impact of AS on HRQoL and medication utilization among adolescents and adults individuals with AS.
Topics: Adult; Adolescent; Humans; Quality of Life; Angelman Syndrome; Surveys and Questionnaires; Depression; Caregivers; Health Status
PubMed: 37039911
DOI: 10.1007/s11136-023-03375-4 -
Frontiers in Pediatrics 2022It is known that the SARS-CoV-2 virus may cause neurologic damage. Rapid-onset obesity, hypoventilation, hypothalamus dysfunction, and autonomic dysregulation (ROHHAD)...
It is known that the SARS-CoV-2 virus may cause neurologic damage. Rapid-onset obesity, hypoventilation, hypothalamus dysfunction, and autonomic dysregulation (ROHHAD) syndrome is a disease of unknown etiology with a progressive course and unclear outcomes. The etiology of ROHHAD syndrome includes genetic, epigenetic, paraneoplastic, and immune-mediated theories, but to our knowledge, viral-associated cases of the disease have not been described yet. Here we present the case of a 4-year-old girl who developed a ROHHAD syndrome-like phenotype after a COVID-19 infection and the results of 5 months of therapy. She had COVID-19 pneumonia, followed by electrolyte disturbances (hypernatremia and hyperchloremia), hypocorticism and hypothyroidism, central hypoventilation-requiring prolonged assisted lung ventilation-bulimia, and progressive obesity with hypertriglyceridemia, dyslipidemia, hyperuricemia, and hyperinsulinemia. The repeated MRI of the brain and hypothalamic-pituitary region with contrast enhancement showed mild post-hypoxic changes. Prader-Willi/Angelman syndrome as well as PHOX2B-associated variants was ruled out. Treatment with non-steroidal anti-inflammatory drugs and monthly courses of intravenous immunoglobulin led to a dramatic improvement. Herein the first description of ROHHAD-like syndrome is timely associated with a previous COVID-19 infection with possible primarily viral or immune-mediated hypothalamic involvement.
PubMed: 35433531
DOI: 10.3389/fped.2022.854367 -
Journal of Clinical Medicine Jun 2024The Angelman Syndrome Registry (RISA) was developed as a retrospective study with the following objectives: to evaluate the clinical history of individuals with...
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. 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. 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. 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.
PubMed: 38930051
DOI: 10.3390/jcm13123520