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Medicina (Kaunas, Lithuania) May 2021We report the second case, to the best of our knowledge, of a mother with Prader-Willi syndrome (PWS) who gave birth to a daughter with Angelman syndrome (AS). The...
We report the second case, to the best of our knowledge, of a mother with Prader-Willi syndrome (PWS) who gave birth to a daughter with Angelman syndrome (AS). The menarche occurred when she was 16, and the following menstrual cycles were irregular, but she never took sexual hormone replacement therapy. At the age of 26, our patient with PWS became pregnant. The diagnosis was confirmed by molecular genetic testing that revealed a ~5.7 Mb deletion in the 15q11.1-15q13 region on the paternal allele in the mother with PWS and the maternal one in the daughter with AS, respectively. Both the mother with PWS and the daughter with AS showed peculiar clinical and genetic features of the two syndromes. Our case report reaffirms the possible fertility in PWS; therefore, it is very important to develop appropriate socio-sexual education programs and fertility assessments in order to guarantee the expression of a healthy sexuality.
Topics: Angelman Syndrome; Female; Fertility; Humans; Prader-Willi Syndrome; Pregnancy
PubMed: 34066798
DOI: 10.3390/medicina57050460 -
Child Psychiatry and Human Development Aug 2021Angelman syndrome (AS) is a complex, heterogeneous, and life-long neurodevelopmental disorder. Despite the considerable impact on individuals and caregivers, no...
Angelman syndrome (AS) is a complex, heterogeneous, and life-long neurodevelopmental disorder. Despite the considerable impact on individuals and caregivers, no disease-modifying treatments are available. To support holistic clinical management and the development of AS-specific outcome measures for clinical studies, we conducted primary and secondary research identifying the impact of symptoms on individuals with AS and their unmet need. This qualitative research adopted a rigorous step-wise approach, aggregating information from published literature, then evaluating it via disease concept elicitation interviews with clinical experts and caregivers. We found that the AS-defining concepts most relevant for treatment included: impaired expressive communication, seizures, maladaptive behavior, cognitive impairment, motor function difficulties, sleep disturbance, and limited self-care abilities. We highlight the relevance of age in experiencing these key AS concepts, and the difference between the perceptions of clinicians and caregivers towards the syndrome. Finally, we outline the impact of AS on individuals, caregivers, and families.
Topics: Angelman Syndrome; Caregivers; Humans; Models, Theoretical; Patient-Centered Care; Qualitative Research
PubMed: 32880036
DOI: 10.1007/s10578-020-01051-z -
Cells Apr 2020Imprinting diseases (IDs) are rare congenital disorders caused by aberrant dosages of imprinted genes. Rare IDs are comprised by a group of several distinct disorders... (Review)
Review
Imprinting diseases (IDs) are rare congenital disorders caused by aberrant dosages of imprinted genes. Rare IDs are comprised by a group of several distinct disorders that share a great deal of homology in terms of genetic etiologies and symptoms. Disruption of genetic or epigenetic mechanisms can cause issues with regulating the expression of imprinted genes, thus leading to disease. Genetic mutations affect the imprinted genes, duplications, deletions, and uniparental disomy (UPD) are reoccurring phenomena causing imprinting diseases. Epigenetic alterations on methylation marks in imprinting control centers (ICRs) also alters the expression patterns and the majority of patients with rare IDs carries intact but either silenced or overexpressed imprinted genes. Canonical CRISPR/Cas9 editing relying on double-stranded DNA break repair has little to offer in terms of therapeutics for rare IDs. Instead CRISPR/Cas9 can be used in a more sophisticated way by targeting the epigenome. Catalytically dead Cas9 (dCas9) tethered with effector enzymes such as DNA de- and methyltransferases and histone code editors in addition to systems such as CRISPRa and CRISPRi have been shown to have high epigenome editing efficiency in eukaryotic cells. This new era of CRISPR epigenome editors could arguably be a game-changer for curing and treating rare IDs by refined activation and silencing of disturbed imprinted gene expression. This review describes major CRISPR-based epigenome editors and points out their potential use in research and therapy of rare imprinting diseases.
Topics: Angelman Syndrome; CRISPR-Cas Systems; DNA Methylation; Diabetes Mellitus; Epigenesis, Genetic; Epigenome; Gene Editing; Genomic Imprinting; Humans; Infant, Newborn, Diseases; Prader-Willi Syndrome; Rare Diseases; Silver-Russell Syndrome
PubMed: 32316223
DOI: 10.3390/cells9040993 -
PloS One 2021Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with absence of speech, happy disposition, frequent laughter,...
Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with absence of speech, happy disposition, frequent laughter, hyperactivity, stereotypies, ataxia and seizures with specific EEG abnormalities. There is a 10-15% of patients with an AS phenotype whose genetic cause remains unknown (Angelman-like syndrome, AS-like). Whole-exome sequencing (WES) was performed on a cohort of 14 patients with clinical features of AS and no molecular diagnosis. As a result, we identified 10 de novo and 1 X-linked pathogenic/likely pathogenic variants in 10 neurodevelopmental genes (SYNGAP1, VAMP2, TBL1XR1, ASXL3, SATB2, SMARCE1, SPTAN1, KCNQ3, SLC6A1 and LAS1L) and one deleterious de novo variant in a candidate gene (HSF2). Our results highlight the wide genetic heterogeneity in AS-like patients and expands the differential diagnosis.
Topics: Adolescent; Adult; Angelman Syndrome; Child; Female; Gene Regulatory Networks; Genetic Association Studies; Genetic Predisposition to Disease; Heat-Shock Proteins; Humans; Infant; Male; Matrix Attachment Region Binding Proteins; Receptors, Cytoplasmic and Nuclear; Repressor Proteins; Transcription Factors; Vesicle-Associated Membrane Protein 2; Exome Sequencing; Young Adult
PubMed: 34653234
DOI: 10.1371/journal.pone.0258766 -
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 -
Neuroscience and Biobehavioral Reviews Feb 2021The pathological alterations that manifest during the early embryonic development due to inherited and acquired factors trigger various neurodevelopmental disorders... (Review)
Review
The pathological alterations that manifest during the early embryonic development due to inherited and acquired factors trigger various neurodevelopmental disorders (NDDs). Besides major NDDs, there are several rare NDDs, exhibiting specific characteristics and varying levels of severity triggered due to genetic and epigenetic anomalies. The rarity of subjects, paucity of neural tissues for detailed analysis, and the unavailability of disease-specific animal models have hampered detailed comprehension of rare NDDs, imposing heightened challenge to the medical and scientific community until a decade ago. The generation of functional neurons and glia through directed differentiation protocols for patient-derived iPSCs, CRISPR/Cas9 technology, and 3D brain organoid models have provided an excellent opportunity and vibrant resource for decoding the etiology of brain development for rare NDDs caused due to monogenic as well as polygenic disorders. The present review identifies cellular and molecular phenotypes demonstrated from patient-derived iPSCs and possible therapeutic opportunities identified for these disorders. New insights to reinforce the existing knowledge of the pathophysiology of these disorders and prospective therapeutic applications are discussed.
Topics: Animals; Cell Differentiation; Humans; Induced Pluripotent Stem Cells; Neurodevelopmental Disorders; Neurons; Prospective Studies
PubMed: 33370574
DOI: 10.1016/j.neubiorev.2020.12.025 -
Molecular Therapy : the Journal of the... Apr 2024Angelman syndrome (AS), an early-onset neurodevelopmental disorder characterized by abnormal gait, intellectual disabilities, and seizures, occurs when the maternal...
Angelman syndrome (AS), an early-onset neurodevelopmental disorder characterized by abnormal gait, intellectual disabilities, and seizures, occurs when the maternal allele of the UBE3A gene is disrupted, since the paternal allele is silenced in neurons by the UBE3A antisense (UBE3A-AS) transcript. Given the importance of early treatment, we hypothesized that prenatal delivery of an antisense oligonucleotide (ASO) would downregulate the murine Ube3a-AS, resulting in increased UBE3A protein and functional rescue. Using a mouse model with a Ube3a-YFP allele that reports on-target ASO activity, we found that in utero, intracranial (IC) injection of the ASO resulted in dose-dependent activation of paternal Ube3a, with broad biodistribution. Accordingly, in utero injection of the ASO in a mouse model of AS also resulted in successful restoration of UBE3A and phenotypic improvements in treated mice on the accelerating rotarod and fear conditioning. Strikingly, even intra-amniotic (IA) injection resulted in systemic biodistribution and high levels of UBE3A reactivation throughout the brain. These findings offer a novel strategy for early treatment of AS using an ASO, with two potential routes of administration in the prenatal window. Beyond AS, successful delivery of a therapeutic ASO into neurons has implications for a clinically feasible prenatal treatment for numerous neurodevelopmental disorders.
Topics: Animals; Mice; Angelman Syndrome; Oligonucleotides, Antisense; Tissue Distribution; Brain; Phenotype; Ubiquitin-Protein Ligases; Disease Models, Animal
PubMed: 38327047
DOI: 10.1016/j.ymthe.2024.02.004 -
Neuroscience Oct 2020Angelman syndrome is a neurodevelopmental disorder presenting with severe deficits in motor, speech, and cognitive abilities. The primary genetic cause of Angelman...
Angelman syndrome is a neurodevelopmental disorder presenting with severe deficits in motor, speech, and cognitive abilities. The primary genetic cause of Angelman syndrome is a maternally transmitted mutation in the Ube3a gene, which has been successfully modeled in Ube3a mutant mice. Phenotypes have been extensively reported in young adult Ube3a mice. Because symptoms continue throughout life in Angelman syndrome, we tested multiple behavioral phenotypes of male Ube3a mice and WT littermate controls at older adult ages. Social behaviors on both the 3-chambered social approach and male-female social interaction tests showed impairments in Ube3a at 12 months of age. Anxiety-related scores on both the elevated plus-maze and the light ↔ dark transitions assays indicated anxiety-like phenotypes in 12 month old Ube3a mice. Open field locomotion parameters were consistently lower at 12 months. Reduced general exploratory locomotion at this age prevented the interpretation of an anxiety-like phenotype, and likely impacted social tasks. Robust phenotypes in middle-aged Ube3a mice appear to result from continued motor decline. Motor deficits may provide the best outcome measures for preclinical testing of pharmacological targets, towards reductions of symptoms in adults with Angelman syndrome.
Topics: Angelman Syndrome; Animals; Behavior Rating Scale; Disease Models, Animal; Female; Male; Mice; Phenotype; Ubiquitin-Protein Ligases
PubMed: 31730795
DOI: 10.1016/j.neuroscience.2019.10.027 -
American Journal of Medical Genetics.... Jul 2023Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual...
Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4-year-old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease-causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4-associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.
Topics: Male; Humans; Angelman Syndrome; Microcephaly; Histones; Intellectual Disability; Phenotype; Neurodevelopmental Disorders; Mutation, Missense
PubMed: 36987712
DOI: 10.1002/ajmg.a.63193 -
PloS One 2020To report and evaluate strabismus surgery in children with Angelman syndrome, in order to optimize and standardize surgical approach. Other purposes are to understand... (Observational Study)
Observational Study
PURPOSE
To report and evaluate strabismus surgery in children with Angelman syndrome, in order to optimize and standardize surgical approach. Other purposes are to understand the possible relation between ocular findings and motor ability, and between improvement in ocular alignment and changes in motor skills in this population.
DESIGN
Observational cross-sectional study.
METHODS
Medical records of pediatric patients with Angelman syndrome, who underwent strabismus surgery, were investigated. Collected data included: genotype, gender, age at the time of surgery, refractive error, pre-operative strabismus, surgical procedure, surgical outcome, gross and fine motor development assessment pre- and post-operatively.
RESULTS
Seventeen subjects, aged 3-15 years, were investigated. Fourteen patients were exotropic, three esotropic. Most patients presented astigmatism. Considering the exaggerated response to standard amounts of surgery and the risk of consecutive strabismus on long term follow-up reported by previous studies in children with developmental delay, a reduction of the amount of strabismus surgery was applied. Post-operatively, all patients presented with a significative reduction of the baseline deviation angle, with all esotropic patients and 7 exotropic patients (59%) achieving orthotropia. The surgical outcomes were variable according to the type and the amount of baseline strabismus, but no case presented with exaggerated surgical response. At baseline, patients showed important delays in all motor abilities, and, post-operatively, presented a significant improvement in walking and fine motor tasks. Pre- and post-operative motor abilities were negatively correlated to astigmatism, anisometropia, and amount of deviation.
CONCLUSIONS
According to our data, the standard nomograms for strabismus surgery may be successfully applied in subjects with Angelman syndrome and exotropia. Our data suggest that the reduction of the deviation angle improves motor skills in strabismic pediatric patients with Angelman syndrome.
Topics: Adolescent; Angelman Syndrome; Child; Child, Preschool; Cross-Sectional Studies; Esotropia; Exotropia; Female; Follow-Up Studies; Humans; Italy; Male; Oculomotor Muscles; Ophthalmologic Surgical Procedures; Postoperative Period; Refraction, Ocular; Retrospective Studies; Strabismus; Treatment Outcome; Vision, Binocular; Visual Acuity; Visual Perception
PubMed: 33186391
DOI: 10.1371/journal.pone.0242366