4,900 results on '"*ANGELMAN syndrome"'
Search Results
2. Long-term Extension of GTX-102 in Angelman Syndrome
- Published
- 2024
3. Study to Investigate the Pharmacokinetics and Safety and to Provide Proof of Mechanism of Alogabat in Children and Adolescents Aged 5-17 Years With Angelman Syndrome (AS) With Deletion Genotype. (Aldebaran)
- Published
- 2024
4. A Study of the Safety and Tolerability of GTX-102 in Children With Angelman Syndrome
- Published
- 2024
5. Parent and Infant Inter(X)Action Intervention (PIXI)
- Author
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University of North Carolina, Chapel Hill
- Published
- 2024
6. Natural History Study for Patients With Angelman Syndrome (NatHisAngelman)
- Author
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Centre Hospitalier Régional de la Citadelle, SYSNAV, and Laurent Servais, Prof. Investigator of CRMN Liège, Principal investigator
- Published
- 2024
7. Study of the Prevalence of Autistic Traits in Angelman Syndrome
- Published
- 2024
8. Structural-functional Connectome in Drug-resistant Epilepsies and Neurodevelopmental Syndromes With Epilepsy
- Published
- 2024
9. Angelman Natural History Study - FAST Spain
- Author
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Parc Taulí Hospital Universitari and BELEN RUIZ-ANTORAN, Principal Investigator
- Published
- 2024
10. A Study To Investigate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of RO7248824 In Participants With Angelman Syndrome
- Published
- 2024
11. Early Check: Expanded Screening in Newborns
- Author
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University of North Carolina, Chapel Hill, The John Merck Fund, Duke University, Wake Forest University, North Carolina Department of Health and Human Services, National Center for Advancing Translational Sciences (NCATS), Cure SMA, The National Fragile X Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Asuragen, Inc., Sarepta Therapeutics, Inc., Muscular Dystrophy Association, The Leona M. and Harry B. Helmsley Charitable Trust, Juvenile Diabetes Research Foundation, Janssen Pharmaceuticals, GeneDx, and Illumina, Inc.
- Published
- 2024
12. HALOS: A Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of Multiple Ascending Doses of ION582 in Participants With Angelman Syndrome
- Author
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Biogen
- Published
- 2024
13. Angelman Syndrome Natural History Study-FAST UK
- Author
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Foundation for Angelman Syndrome Therapeutics UK and Hoffmann-La Roche
- Published
- 2024
14. The Global Angelman Syndrome Registry (GASR)
- Author
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Queensland University of Technology and Associate Professor Helen (Honey) Heussler, Associate Professor, Paediatrics and Child Health
- Published
- 2024
15. Italian Angelman Syndrome Registry Protocol (RISA)
- Published
- 2024
16. A Study of OV101 in Individuals With Angelman Syndrome (AS) (NEPTUNE)
- Published
- 2024
17. Angelman syndrome in Poland: current diagnosis and therapy status—the caregiver perspective: a questionnaire study.
- Author
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Suleja, Agata, Milska-Musa, Katarzyna, Przysło, Łukasz, Bednarczyk, Marzena, Kostecki, Marcin, Cysewski, Dominik, Matryba, Paweł, Rozensztrauch, Anna, Dwornik, Michał, Opacki, Marcin, Śmigiel, Robert, and Łukasiewicz, Kacper
- Abstract
Background: Angelman syndrome (AS) is a rare neurodevelopmental disease caused by imprinting disorders that impede the production of the ubiquitin E3A ligase protein (UBE3A). AS affects multiple systems, with the main symptoms including epilepsy, psychomotor disorders and speech development disorders. To date, no study has been conducted in the Polish population to verify the condition's diagnosis and treatment process. Results: Seventy patients with the median age of 60 months were included into the analysis. 80% of patients were diagnosed with deletion, 19.9% with a mutation of UBE3A gene, 4.3% with paternal uniparental disomy (UPD) and 2.8% with an imprinting defect. The mean age of first symptoms was 5 months, while the mean age of diagnosis was 29 months (earliest in deletion group at 23 months), and the median duration of diagnosis process was 7 months. The average time to a clinical geneticist appointment was 3 months. 37.9% of the patients initially received a different diagnosis. Epileptic seizures were present in 88.6% of the individuals. 98.6% of the studied group were under care of a pediatric neurologist, 47.1% of a gastroenterologist. A ketogenic diet was used in 7.1% of patients. Caregivers identified finding a specialist suitable for AS patients and access to genetic testing as the biggest problems. Conclusions: The care of patients with AS in Poland is carried out according to the European and world standards, however there is an impeded access to clinical geneticist, and the knowledge about rare diseases among primary healthcare physicians could be improved. Moreover, access to AS care specialists and coordination of care is limited. There is a need for creation a specialized centers and databases for AS patients. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
18. Epigenetics in rare neurological diseases.
- Author
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Roberts, Chris-Tiann, Arezoumand, Khatereh Saei, Shahib, Ashraf Kadar, Davie, James R., and Rastegar, Mojgan
- Subjects
HUNTINGTON disease ,PRADER-Willi syndrome ,NEUROLOGICAL disorders ,RETT syndrome ,ANGELMAN syndrome - Abstract
Rare neurological diseases include a vast group of heterogenous syndromes with primary impairment(s) in the peripheral and/or central nervous systems. Such rare disorders may have overlapping phenotypes, despite their distinct genetic etiology. One unique aspect of rare neurological diseases is their potential common association with altered epigenetic mechanisms. Epigenetic mechanisms include regulatory processes that control gene expression and cellular phenotype without changing the composition of the corresponding DNA sequences. Epigenetic factors include three types of proteins, the "readers, writers, and erasers" of DNA and DNA-bound proteins. Thus, epigenetic impairments of many neurological diseases may contribute to their pathology and manifested phenotypes. Here, we aim to provide a comprehensive review on the general etiology of selected rare neurological diseases, that include Rett Syndrome, Prader-Willi Syndrome, Rubinstein-Taybi Syndrome, Huntington's disease, and Angelman syndrome, with respect to their associated aberrant epigenetic mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
19. Evaluation of an In-House Genetic Testing Method for Confirming Prader-Willi and Angelman Syndromes in Sri Lanka.
- Author
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Kugalingam, Nirosha, de Silva, Deepthi, Rathnayake, Pyara, Atapattu, Navoda, Ranaweera, Dinali M., and Chandrasekharan, Naduviladath V.
- Subjects
PRADER-Willi syndrome ,GENETIC testing ,ANGELMAN syndrome ,TEST methods ,GENETIC counseling ,INTERFERON beta 1b - Abstract
Background: Prader-Willi syndrome (PWS, MIM 176,270) and Angelman syndrome (AS, MIM 105,830) are caused by imprinting defects of chromosome 15q11-13, with loss of maternal gene expression causing AS and paternal gene expression causing PWS. The diagnosis, once established in most cases by using a methylation-specific PCR test, enables appropriate therapeutic interventions and avoids the need for further investigations. Genetic testing for PWS/AS is limited in Sri Lanka (and in other low- and middle-income countries), mainly because parents are unable to pay for testing as these are not funded by the health service. Methods: Ninety cases (46 female) with clinical features suggesting PWS (n = 37) and AS (n = 53), referred by a pediatric endocrinologist and a pediatric neurologist, were recruited. Clinical information and blood samples were obtained following informed consent. DNA was extracted and methylation-specific PCR (MS-PCR) was performed following bisulfite modification of DNA by using an in-house method and a kit. Results were validated using known positive controls. Parent-child trio DNA samples were used in cases with confirmed PWS and AS to determine if the disease was due to a deletion or uniparental disomy. The cost of the MS-PCR testing of the two modification methods and the microsatellite analysis was determined. Results: Among the suspected PWS cases, 19/37 were positive, while 5/53 of the suspected AS cases were positive. The lower identification rate of AS is probably related to the overlap of clinical features of this condition with other disorders. The kit-based modification method was more reliable, less time-consuming, and cost-effective in our laboratory. Conclusions: The kit-based modification followed by MS-PCR described in this study enables more affordable genetic testing of suspected PWS/AS cases, and this is likely to improve patient care by targeting appropriate therapy for the affected cases. Parental genetic counselling is made possible regarding the low recurrence risk, especially where a deletion or uniparental disomy is confirmed. In MS-PCR, negative cases with a strong clinical suspicion of AS, UBE3A mutation testing is required. In addition, imprinting center mutation/deletion testing may also be needed in strongly clinically suspected, MS-PCR negative PWS and AS cases. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
20. Epilepsy, EEG and chromosomal rearrangements.
- Author
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Paprocka, Justyna, Coppola, Antonietta, Cuccurullo, Claudia, Stawicka, Elżbieta, and Striano, Pasquale
- Subjects
FRAGILE X syndrome ,CHROMOSOMAL rearrangement ,ANGELMAN syndrome ,SYMPTOMS ,LITERATURE reviews ,ELECTROENCEPHALOGRAPHY - Abstract
Chromosomal abnormalities are associated with a broad spectrum of clinical manifestations, one of the more commonly observed of which is epilepsy. The frequency, severity, and type of epileptic seizures vary according to the macro‐ and microrearrangements present. Even within a single chromosomal anomaly, we most often deal with a phenotypic spectrum. The aim of the study was to look for chromosomal rearrangements with a characteristic electroencephalographic pattern. Only a few disorders have peculiar electroclinical abnormalities: 1p36, 4p16, 6q terminal or trisomy 12p, Angelman syndrome, inv dup 15, 15q13.3 deletions, ring 20, Down syndrome, or Xp11.22–11.23 duplication. We also reviewed studies on epileptic seizures and typical electroencephalographic patterns described in certain chromosomal rearrangements, focusing on the quest for potential electroclinical biomarkers. The comprehensive review concludes with clinical presentations of the most common micro and macro chromosomal rearrangements, such as 17q21.31 microdeletion, 6q terminal deletion, 15q inv dup syndrome, 2q24.4 deletion, Xp11.22–11.23 duplication, 15q13.3 microdeletion, 1p36 terminal deletion, 5q14.3 microdeletion, and Xq28 duplication. The papers reviewed did not identify any specific interictal electroencephalographic patterns that were unique and significant biomarkers for a given chromosomal microrearrangement. The types of seizures described varied, with both generalized and focal seizures of various morphologies being reported. Patients with chromosomal anomalies may also meet the criteria for specific epileptic syndromes such as Infantile Epilepsy Spasms Syndrome (IESS, West syndrome): 16p13.11, 15q13.3 and 17q21.31 microdeletions, 5q inv dup. syndrome; Dravet syndrome (2q24.4 deletion), Lennox–Gastaut syndrome (15q11 duplication. 1q13.3, 5q inv dup.); or Self‐Limited Epilepsy with Autonomic Features (SeLEAS, Panayiotopoulos syndrome: terminal deletion of 6q.n), Self‐Limited Epilepsy with Centrotemporal Spikes (SeLECT): fragile X syndrome. It is essential to better characterize groups of patients to more accurately define patterns of epilepsy and EEG abnormalities. This could lead to new treatment strategies. Future research is required to better understand epileptic syndromes and chromosomal rearrangements. Plain Language Summary: This paper presents EEG recording abnormalities in patients with various gene abnormalities that can cause epilepsy. The authors summarize these EEG variations based on a literature review to see if they occur frequently enough in other chromosomal abnormalities (in addition to those already known) to be a clue for further diagnosis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
21. 1H-NMR-based metabolomics reveals metabolic alterations in early development of a mouse model of Angelman syndrome.
- Author
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Gupta, Pooja Kri, Barak, Sharon, Feuermann, Yonatan, Goobes, Gil, and Kaphzan, Hanoch
- Subjects
ANGELMAN syndrome ,PROTON magnetic resonance ,METABOLOMICS ,LABORATORY mice ,METABOLOMIC fingerprinting - Abstract
Background: Angelman syndrome (AS) is a rare neurodevelopmental genetic disorder caused by the loss of function of the ubiquitin ligase E3A (UBE3A) gene, affecting approximately 1:15,000 live births. We have recently shown that mitochondrial function in AS is altered during mid to late embryonic brain development leading to increased oxidative stress and enhanced apoptosis of neural precursor cells. However, the overall alterations of metabolic processes are still unknown. Hence, as a follow-up, we aim to investigate the metabolic profiles of wild-type (WT) and AS littermates and to identify which metabolic processes are aberrant in the brain of AS model mice during embryonic development. Methods: We collected brain tissue samples from mice embryos at E16.5 and performed metabolomic analyses using proton nuclear magnetic resonance (
1 H-NMR) spectroscopy. Multivariate and Univariate analyses were performed to determine the significantly altered metabolites in AS mice. Pathways associated with the altered metabolites were identified using metabolite set enrichment analysis. Results: Our analysis showed that overall, the metabolomic fingerprint of AS embryonic brains differed from those of their WT littermates. Moreover, we revealed a significant elevation of distinct metabolites, such as acetate, lactate, and succinate in the AS samples compared to the WT samples. The elevated metabolites were significantly associated with the pyruvate metabolism and glycolytic pathways. Limitations: Only 14 metabolites were successfully identified and investigated in the present study. The effect of unidentified metabolites and their unresolved peaks was not determined. Additionally, we conducted the metabolomic study on whole brain tissue samples. Employing high-resolution NMR studies on different brain regions could further expand our knowledge regarding metabolic alterations in the AS brain. Furthermore, increasing the sample size could reveal the involvement of more significantly altered metabolites in the pathophysiology of the AS brain. Conclusions: Ube3a loss of function alters bioenergy-related metabolism in the AS brain during embryonic development. Furthermore, these neurochemical changes could be linked to the mitochondrial reactive oxygen species and oxidative stress that occurs during the AS embryonic development. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
22. A clinical-translational review of sleep problems in neurodevelopmental disabilities.
- Author
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Peters, Sarika U., Shelton, Althea Robinson, Malow, Beth A., and Neul, Jeffrey L.
- Subjects
SLEEP ,SLEEP interruptions ,NEURAL development ,AUTISM spectrum disorders ,RETT syndrome ,CHILDREN with autism spectrum disorders - Abstract
Sleep disorders are very common across neurodevelopmental disorders and place a large burden on affected children, adolescents, and their families. Sleep disturbances seem to involve a complex interplay of genetic, neurobiological, and medical/environmental factors in neurodevelopmental disorders. In this review, we discuss animal models of sleep problems and characterize their presence in two single gene disorders, Rett Syndrome, and Angelman Syndrome and two more commonly occurring neurodevelopmental disorders, Down Syndrome, and autism spectrum disorders. We then discuss strategies for novel methods of assessment using wearable sensors more broadly for neurodevelopmental disorders in general, including the importance of analytical validation. An increased understanding of the mechanistic contributions and potential biomarkers of disordered sleep may offer quantifiable targets for interventions that improve overall quality of life for affected individuals and their families. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
23. Ube3a unsilencer for the potential treatment of Angelman syndrome.
- Author
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Vihma, Hanna, Li, Kelin, Welton-Arndt, Anna, Smith, Audrey L., Bettadapur, Kiran R., Gilmore, Rachel B., Gao, Eric, Cotney, Justin L., Huang, Hsueh-Cheng, Collins, Jon L., Chamberlain, Stormy J., Lee, Hyeong-Min, Aubé, Jeffrey, and Philpot, Benjamin D.
- Subjects
ANGELMAN syndrome ,SMALL molecules ,RESEARCH personnel ,DELETION mutation ,GENE silencing ,LABORATORY mice - Abstract
Deletion of the maternal UBE3A allele causes Angelman syndrome (AS); because paternal UBE3A is epigenetically silenced by a long non-coding antisense (UBE3A-ATS) in neurons, this nearly eliminates UBE3A protein in the brain. Reactivating paternal UBE3A holds promise for treating AS. We previously showed topoisomerase inhibitors can reactivate paternal UBE3A, but their therapeutic challenges prompted our search for small molecule unsilencers with a different mechanism of action. Here, we found that (S)-PHA533533 acts through a novel mechanism to significantly increase paternal Ube3a mRNA and UBE3A protein levels while downregulating Ube3a-ATS in primary neurons derived from AS model mice. Furthermore, peripheral delivery of (S)-PHA533533 in AS model mice induces widespread neuronal UBE3A expression. Finally, we show that (S)-PHA533533 unsilences paternal UBE3A in AS patient-derived neurons, highlighting its translational potential. Our findings provide a lead for developing a small molecule treatment for AS that could be safe, non-invasively delivered, and capable of brain-wide unsilencing of paternal UBE3A. Angelman syndrome is a neurodevelopmental disorder caused by the deletion of a single gene. Here, researchers discovered a small molecule that could be delivered peripherally to activate a dormant copy of the gene throughout the brain, providing a potential treatment opportunity. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
24. Parents' preferences for receiving and discussing prognostic genetic information regarding their children's neurodevelopmental condition: A qualitative study.
- Author
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Turbitt, Erin, Bourne, Meg, McEwen, Alison, and Amor, David J.
- Subjects
DESPAIR ,FRAGILE X syndrome ,PARENTS ,NEURAL development ,TECHNOLOGICAL innovations ,ANGELMAN syndrome - Abstract
Aim: To investigate parents' preferences and motivations for receiving and discussing prognostic genetic test results. Method: We used a cross‐sectional, interpretive description qualitative study design. We collected data through semi‐structured interviews with Australian parents, which we analysed using reflexive thematic analysis. Results: Parents (n = 32) had a child or children with a genetic neurodevelopmental condition, such as fragile X syndrome, DiGeorge (22q11.2 deletion) syndrome, or Angelman syndrome. Parents of mildly impacted or older children were tolerant to prognostic uncertainty. Parents found conversations about their child's prognosis emotional and preferred to discuss their child's potential strengths and challenges. While most were enthusiastic about prognostic tests and described many motivations for testing, the potential for prognostic information to contribute to a loss of hope and stigmatizing societal views were also discussed. Interpretation: Parents had mixed preferences and motivations for acquiring prognostic genetic information about their child, contrasting evidence in other contexts such as cancer where parents typically have minimal tolerance of uncertainty. Health professionals should consider strength‐based framing of prognostic information gained from current and emerging technologies when returning results to families. What this paper adds: Parents had varied views about receiving prognostic information on their children's neurodevelopmental condition.Some parents preferred prognostic uncertainty about their children's genetic neurodevelopmental condition. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
25. Exploring the Clinical and Genetic Landscape of Angelman Syndrome: Patient-Reported Insights from an Italian Registry.
- Author
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Carriero, Pier Luigi, Zangari, Rosalia, Sfreddo, Eleonora, Ghirardi, Arianna, Schieppati, Arrigo, Barbui, Tiziano, and Biroli, Francesco
- Subjects
ANGELMAN syndrome ,EPILEPSY ,SLEEP ,MEDICAL registries ,SEIZURES (Medicine) ,DEVELOPMENTAL delay - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
26. Developmental milestones and daily living skills in individuals with Angelman syndrome.
- Author
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Sadhwani, Anjali, Powers, Sonya, Wheeler, Anne, Miller, Hillary, Potter, Sarah Nelson, Peters, Sarika U., Bacino, Carlos A., Skinner, Steven A., Wink, Logan K., Erickson, Craig A., Bird, Lynne M., and Tan, Wen-Hann
- Subjects
LIFE skills ,ANGELMAN syndrome ,GROSS motor ability ,PROPORTIONAL hazards models ,FINE motor ability - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
27. Regional and cellular organization of the autism-associated protein UBE3A/E6AP and its antisense transcript in the brain of the developing rhesus monkey.
- Author
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Ramirez, Chavely Gonzalez, Salvador, Sarah G., Rekha Patel, Ridthi Kartik, Clark, Sarah, Miller, Noah W., James, Lucas M., Ringelberg, Nicholas W., Simon, Jeremy M., Bennett, Jeffrey, Amaral, David G., Burette, Alain C., and Philpot, Benjamin D.
- Subjects
RHESUS monkeys ,REGIONALISM (International organization) ,ANGELMAN syndrome ,NEURON development ,NEUROGLIA ,GENE silencing ,GESTATIONAL age - Abstract
Angelman syndrome (AS) is a neurogenetic disorder caused by mutations or deletions in the maternally-inherited UBE3A allele, leading to a loss of UBE3A protein expression in neurons. The paternally-inherited UBE3A allele is epigenetically silenced in neurons during development by a noncoding transcript (UBE3A-ATS). The absence of neuronal UBE3A results in severe neurological symptoms, including speech and language impairments, intellectual disability, and seizures. While no cure exists, therapies aiming to restore UBE3A function--either by gene addition or by targeting UBE3A-ATS--are under development. Progress in developing these treatments relies heavily on inferences drawn from mouse studies about the function of UBE3A in the human brain. To aid translational efforts and to gain an understanding of UBE3A and UBE3A-ATS biology with greater relevance to human neurodevelopmental contexts, we investigated UBE3A and UBE3A-ATS expression in the developing brain of the rhesus macaque, a species that exhibits complex social behaviors, resembling aspects of human behavior to a greater degree than mice. Combining immunohistochemistry and in situ hybridization, we mapped UBE3A and UBE3A-ATS regional and cellular expression in normal prenatal, neonatal, and adolescent rhesus macaque brains. We show that key hallmarks of UBE3A biology, well-known in rodents, are also present in macaques, and suggest paternal UBE3A silencing in neurons--but not glial cells--in the macaque brain, with onset between gestational day 48 and 100. These findings support proposals that early-life, perhaps even prenatal, intervention is optimal for overcoming the maternal allele loss of UBE3A linked to AS. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
28. Short Stature and Distinct Growth Characteristics in Angelman Syndrome.
- Author
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Gruber, Noah, Daka, Ayman, Lapidot, Noy, Modan-Moses, Dalit, Pinhas-Hamiel, Orit, Ben Zeev, Bruria, and Heimer, Gali
- Subjects
ANGELMAN syndrome ,SLEEP ,MOTOR ability ,SPEECH ,FAMILY history (Medicine) - Abstract
Introduction: 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 were 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 versus 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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
29. Angelman Syndrome Video Assessment (ASVA) Source Material Study (ASVA SMS)
- Author
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Ionis Pharmaceuticals, Inc. and Boston Children's Hospital
- Published
- 2023
30. Angelman syndrome in Poland: current diagnosis and therapy status—the caregiver perspective: a questionnaire study
- Author
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Agata Suleja, Katarzyna Milska-Musa, Łukasz Przysło, Marzena Bednarczyk, Marcin Kostecki, Dominik Cysewski, Paweł Matryba, Anna Rozensztrauch, Michał Dwornik, Marcin Opacki, Robert Śmigiel, and Kacper Łukasiewicz
- Subjects
Angelman syndrome ,Rase diseases ,Healthcare organisation ,Genetic testing ,Medicine - Abstract
Abstract Background Angelman syndrome (AS) is a rare neurodevelopmental disease caused by imprinting disorders that impede the production of the ubiquitin E3A ligase protein (UBE3A). AS affects multiple systems, with the main symptoms including epilepsy, psychomotor disorders and speech development disorders. To date, no study has been conducted in the Polish population to verify the condition's diagnosis and treatment process. Results Seventy patients with the median age of 60 months were included into the analysis. 80% of patients were diagnosed with deletion, 19.9% with a mutation of UBE3A gene, 4.3% with paternal uniparental disomy (UPD) and 2.8% with an imprinting defect. The mean age of first symptoms was 5 months, while the mean age of diagnosis was 29 months (earliest in deletion group at 23 months), and the median duration of diagnosis process was 7 months. The average time to a clinical geneticist appointment was 3 months. 37.9% of the patients initially received a different diagnosis. Epileptic seizures were present in 88.6% of the individuals. 98.6% of the studied group were under care of a pediatric neurologist, 47.1% of a gastroenterologist. A ketogenic diet was used in 7.1% of patients. Caregivers identified finding a specialist suitable for AS patients and access to genetic testing as the biggest problems. Conclusions The care of patients with AS in Poland is carried out according to the European and world standards, however there is an impeded access to clinical geneticist, and the knowledge about rare diseases among primary healthcare physicians could be improved. Moreover, access to AS care specialists and coordination of care is limited. There is a need for creation a specialized centers and databases for AS patients.
- Published
- 2024
- Full Text
- View/download PDF
31. 1H-NMR-based metabolomics reveals metabolic alterations in early development of a mouse model of Angelman syndrome
- Author
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Pooja Kri Gupta, Sharon Barak, Yonatan Feuermann, Gil Goobes, and Hanoch Kaphzan
- Subjects
Angelman syndrome ,Metabolite ,Mitochondria ,Reactive oxygen species ,Developmental disorders ,Lactate ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Angelman syndrome (AS) is a rare neurodevelopmental genetic disorder caused by the loss of function of the ubiquitin ligase E3A (UBE3A) gene, affecting approximately 1:15,000 live births. We have recently shown that mitochondrial function in AS is altered during mid to late embryonic brain development leading to increased oxidative stress and enhanced apoptosis of neural precursor cells. However, the overall alterations of metabolic processes are still unknown. Hence, as a follow-up, we aim to investigate the metabolic profiles of wild-type (WT) and AS littermates and to identify which metabolic processes are aberrant in the brain of AS model mice during embryonic development. Methods We collected brain tissue samples from mice embryos at E16.5 and performed metabolomic analyses using proton nuclear magnetic resonance (1H-NMR) spectroscopy. Multivariate and Univariate analyses were performed to determine the significantly altered metabolites in AS mice. Pathways associated with the altered metabolites were identified using metabolite set enrichment analysis. Results Our analysis showed that overall, the metabolomic fingerprint of AS embryonic brains differed from those of their WT littermates. Moreover, we revealed a significant elevation of distinct metabolites, such as acetate, lactate, and succinate in the AS samples compared to the WT samples. The elevated metabolites were significantly associated with the pyruvate metabolism and glycolytic pathways. Limitations Only 14 metabolites were successfully identified and investigated in the present study. The effect of unidentified metabolites and their unresolved peaks was not determined. Additionally, we conducted the metabolomic study on whole brain tissue samples. Employing high-resolution NMR studies on different brain regions could further expand our knowledge regarding metabolic alterations in the AS brain. Furthermore, increasing the sample size could reveal the involvement of more significantly altered metabolites in the pathophysiology of the AS brain. Conclusions Ube3a loss of function alters bioenergy-related metabolism in the AS brain during embryonic development. Furthermore, these neurochemical changes could be linked to the mitochondrial reactive oxygen species and oxidative stress that occurs during the AS embryonic development.
- Published
- 2024
- Full Text
- View/download PDF
32. A clinical-translational review of sleep problems in neurodevelopmental disabilities
- Author
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Sarika U. Peters, Althea Robinson Shelton, Beth A. Malow, and Jeffrey L. Neul
- Subjects
Sleep ,Neurodevelopmental disabilities ,Animal models ,Rett syndrome ,Angelman syndrome ,Down syndrome ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract Sleep disorders are very common across neurodevelopmental disorders and place a large burden on affected children, adolescents, and their families. Sleep disturbances seem to involve a complex interplay of genetic, neurobiological, and medical/environmental factors in neurodevelopmental disorders. In this review, we discuss animal models of sleep problems and characterize their presence in two single gene disorders, Rett Syndrome, and Angelman Syndrome and two more commonly occurring neurodevelopmental disorders, Down Syndrome, and autism spectrum disorders. We then discuss strategies for novel methods of assessment using wearable sensors more broadly for neurodevelopmental disorders in general, including the importance of analytical validation. An increased understanding of the mechanistic contributions and potential biomarkers of disordered sleep may offer quantifiable targets for interventions that improve overall quality of life for affected individuals and their families.
- Published
- 2024
- Full Text
- View/download PDF
33. Enabling endpoint development for interventional clinical trials in individuals with Angelman syndrome: a prospective, longitudinal, observational clinical study (FREESIAS).
- Author
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Tjeertes, Jorrit, Bacino, Carlos, Bichell, Terry, Bustamante, Mariana, Crean, Rebecca, Jeste, Shafali, Komorowski, Robert, Krishnan, Michelle, Miller, Meghan, Nobbs, David, Ochoa-Lubinoff, Cesar, Parkerson, Kimberly, Rotenberg, Alexander, Sadhwani, Anjali, Shen, Mark, Squassante, Lisa, Tan, Wen-Hann, Vincenzi, Brenda, Wheeler, Anne, Hipp, Joerg, Berry-Kravis, Elizabeth, and Bird, Lynne
- Subjects
Angelman syndrome ,Clinical outcome assessments ,Clinical trials ,Digital health technology ,EEG ,Endpoint development ,Natural history ,Sleep ,UBE3A ,Humans ,Angelman Syndrome ,Prospective Studies ,Pandemics ,COVID-19 ,Electroencephalography - Abstract
BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of a functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported the results from the FREESIAS study assessing the feasibility and utility of in-clinic and at-home measures of key AS symptoms. METHODS: Fifty-five individuals with AS (aged
- Published
- 2023
34. Quantitative measures of motor development in Angelman syndrome
- Author
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Duis, Jessica, Skinner, Austin, Carson, Robert, Gouelle, Arnaud, Annoussamy, Melanie, Silverman, Jill L, Apkon, Susan, Servais, Laurent, and Carollo, James
- Subjects
Biological Sciences ,Biomedical and Clinical Sciences ,Clinical Sciences ,Genetics ,Rare Diseases ,Intellectual and Developmental Disabilities (IDD) ,Neurodegenerative ,Brain Disorders ,Rehabilitation ,Physical Rehabilitation ,Neurosciences ,Clinical Research ,Humans ,Angelman Syndrome ,Cross-Sectional Studies ,Walking ,Gait ,Knee Joint ,Biomechanical Phenomena ,Angelman syndrome ,gait ,genetics ,movement disorders ,muscle spasticity ,neurodevelopmental disabilities ,outcome measures ,Clinical sciences - Abstract
Angelman Syndrome is a rare neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, characteristic behavior, and movement disorders. Clinical gait analysis provides the opportunity for movement quantification to investigate an observed maladaptive change in gait pattern and offers an objective outcome of change. Pressure-sensor-based technology, inertial and activity monitoring, and instrumented gait analysis (IGA) were employed to define motor abnormalities in Angelman syndrome. Temporal-spatial gait parameters of persons with Angelman Syndrome (pwAS) show deficiencies in gait performance through walking speed, step length, step width, and walk ratio. pwAS walk with reduced step lengths, increased step width, and greater variability. Three-dimensional motion kinematics showed increased anterior pelvic tilt, hip flexion, and knee flexion. PwAS have a walk ratio more than two standard deviations below controls. Dynamic electromyography showed prolonged activation of knee extensors, which was associated with a decreased range of motion and the presence of hip flexion contractures. Use of multiple gait tracking modalities revealed that pwAS exhibit a change in gait pattern to a flexed knee gait pattern. Cross-sectional studies of individuals with AS show a regression toward this maladaptive gait pattern over development in pwAS ages 4-11. PwAS unexpectedly did not have spasticity associated with change in gait pattern. Multiple quantitative measures of motor patterning may offer early biomarkers of gait decline consistent with critical periods of intervention, insight into appropriate management strategies, objective primary outcomes, and early indicators of adverse events.
- Published
- 2023
35. Colin Farrell: 'I Just Think He's Magic'.
- Author
-
JORDAN, JULIE
- Subjects
YOUNG adults ,LEARNING curve ,ANGELMAN syndrome ,PARENTS ,MOTHERS ,BEACHES - Abstract
Colin Farrell, the actor, has opened up about his son James, who has Angelman syndrome, a rare genetic disorder causing severe developmental and neurological disabilities. Farrell is starting a foundation to support individuals with Angelman syndrome and other intellectual disabilities. The foundation aims to address the chronic underfunding and resource shortages in the Home and Community-Based Waiver system, which provides long-term support for individuals with disabilities. Farrell hopes to ensure that every person living with an intellectual disability has an enriched and meaningful existence within their own communities. [Extracted from the article]
- Published
- 2024
36. Promoting Prosocial Behavior in Syndromic Intellectual and Developmental Disabilities
- Author
-
Emory University
- Published
- 2023
37. Development of a Newborn Screening Assay for Angelman Syndrome and Prader-Willi Syndrome
- Author
-
Ultragenyx Pharmaceutical Inc
- Published
- 2023
38. NanoImprint: A DNA methylation tool for clinical interpretation and diagnosis of common imprinting disorders using nanopore long‐read sequencing.
- Author
-
Bækgaard, Caroline Hey, Lester, Emilie Boye, Møller‐Larsen, Steffen, Lauridsen, Mathilde Faurholdt, and Larsen, Martin Jakob
- Subjects
WHOLE genome sequencing ,DNA methylation ,ANGELMAN syndrome ,METHYLATION ,EPIGENETICS - Abstract
Introduction: Long‐read whole genome sequencing like Oxford Nanopore Technology, is increasingly being introduced in clinical settings. With its ability to simultaneously call sequence variation and DNA modifications including 5‐methylcytosine, nanopore is a promising technology to improve diagnostics of imprinting disorders. Methods: Currently, no tools to analyze DNA methylation patterns at known clinically relevant imprinted regions are available. Here we present NanoImprint, which generates an easily interpretable report, based on long‐read nanopore sequencing, to use for identifying clinical relevant abnormalities in methylation levels at 14 imprinted regions and diagnosis of common imprinting disorders. Results and conclusion: NanoImprint outputs a summarizing table and visualization plots displays methylation frequency (%) and chromosomal positions for all regions, with phased data color‐coded for the two alleles. We demonstrate the utility of NanoImprint using three imprinting disorder samples from patients with Beckwith‐Wiedemann syndrome (BWS), Angelman syndrome (AS) and Prader‐Willi syndrome (PWS). NanoImprint script is available from https://github.com/carolinehey/NanoImprint. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
39. Understanding reliability of the observer-reported communication ability measure within Angelman syndrome through the lens of generalizability theory
- Author
-
Dandan Chen, Christina K. Zigler, Li Lin, Nicole Lucas, Molly McFatrich, Jennifer Panagoulias, Allyson Berent, and Bryce B. Reeve
- Subjects
Angelman syndrome ,Reliability ,Generalizability theory ,Communication ,Caregivers ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract Aims Caregivers rate improved communication ability as one of the most desired outcomes for successful interventions for individuals with Angelman syndrome (AS). When measuring communication ability in clinical trials, the reliability of such measures is critical for detecting significant changes over time. This study examined the reliability of the Observed-Reported Communication Ability (ORCA) measure completed by caregivers of individuals with AS. Methods The ORCA measure was completed by 249 caregivers with 170 caregivers completing the ORCA measure again after 5–12 days. Generalizability theory was used to examine the following sources of measurement error in ORCA scores: concepts, subdomains, assessment points, and the interactions among those facets and the object of measurement: communication ability. Three generalizability studies were conducted to understand the reliability of the ORCA measure for different measurement designs. Decision studies were carried out to demonstrate the optimization of measurement procedures of the ORCA measure. Results G and Phi coefficients of the original measurement design exceeded the 0.80 threshold considered sufficiently reliable to make relative and absolute decisions about the communication ability of individuals with AS based on their caregivers’ observed scores. The optimization procedures indicated that increasing the number of communication concepts and/or assessment points leads to more reliable estimates of communication. Conclusion The ORCA measure was able to reliably distinguish different levels of communication ability among individuals with AS. Multiple assessment points and or more concepts would provide more precise estimates of an individual’s communication ability but at the cost of survey fatigue.
- Published
- 2024
- Full Text
- View/download PDF
40. Sleep disturbance in Angelman syndrome patients
- Author
-
Song Qu, Junyi Wang, Xingying Guan, Cui Song, and Yanyan Wang
- Subjects
Angelman syndrome ,Sleep disturbance ,Imprinting disorder ,Medicine - Abstract
Abstract Angelman syndrome (AS) is a neurodevelopmental disorder caused by abnormal expression of the maternal ubiquitin protein ligase E3A gene (UBE3A). As one of the most challenging symptoms and important focuses of new treatment, sleep disturbance is reported to occur in 70–80% of patients with AS and has a serious impact on the lives of patients and their families. Although clinical studies and animal model studies have provided some clues, recent research into sleep disorders in the context of AS is still very limited. It is generally accepted that there is an interaction between neurodevelopment and sleep; however, there is no recognized mechanism for sleep disorders in AS patients. Accordingly, there are no aetiologically specific clinical treatments for AS-related sleep disorders. The most common approaches involve ameliorating symptoms through methods such as behavioural therapy and symptomatic pharmacotherapy. In recent years, preclinical and clinical studies on the targeted treatment of AS have emerged. Although precision therapy for restoring the UBE3A level and the function of its signalling pathways is inevitably hindered by many remaining obstacles, this approach has the potential to address AS-related sleep disturbance.
- Published
- 2024
- Full Text
- View/download PDF
41. Outcome measures in Angelman syndrome
- Author
-
Doesjka A. Hagenaar, Karen G. C. B. Bindels-de Heus, Maud M. van Gils, Louise van den Berg, Leontine W. ten Hoopen, Philine Affourtit, Johan J. M. Pel, Koen F. M. Joosten, Manon H. J. Hillegers, Henriëtte A. Moll, Marie-Claire Y. de Wit, Gwen C. Dieleman, and Sabine E. Mous
- Subjects
Angelman syndrome ,Outcome measures ,Eye-tracking ,Functional near-Infrared Spectroscopy ,Indirect calorimetry ,Bio-impedance analysis ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Abstract Background Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems, emotional/behavioral challenges, and a tendency towards hyperphagia and weight gain. The characteristics of AS make it difficult to measure these children’s functioning with standard clinical tests. Feasible outcome measures are needed to measure current functioning and change over time, in clinical practice and clinical trials. Aim Our first aim is to assess the feasibility of several functional tests. We target domains of neurocognitive functioning and physical growth using the following measurement methods: eye-tracking, functional Near-Infrared Spectroscopy (fNIRS), indirect calorimetry, bio-impedance analysis (BIA), and BOD POD (air-displacement plethysmography). Our second aim is to explore the results of the above measures, in order to better understand the AS phenotype. Methods The study sample consisted of 28 children with AS aged 2–18 years. We defined an outcome measure as feasible when (1) at least 70% of participants successfully finished the measurement and (2) at least 60% of those participants had acceptable data quality. Adaptations to the test procedure and reasons for early termination were noted. Parents rated acceptability and importance and were invited to make recommendations to increase feasibility. The results of the measures were explored. Results Outcome measures obtained with eye-tracking and BOD POD met the definition of feasibility, while fNIRS, indirect calorimetry, and BIA did not. The most important reasons for early termination of measurements were showing signs of protest, inability to sit still and poor/no calibration (eye-tracking specific). Post-calibration was often applied to obtain valid eye-tracking results. Parents rated the BOD POD als most acceptable and fNIRS as least acceptable for their child. All outcome measures were rated to be important. Exploratory results indicated longer reaction times to high salient visual stimuli (eye-tracking) as well as high body fat percentage (BOD POD). Conclusions Eye-tracking and BOD POD are feasible measurement methods for children with AS. Eye-tracking was successfully used to assess visual orienting functions in the current study and (with some practical adaptations) can potentially be used to assess other outcomes as well. BOD POD was successfully used to examine body composition. Trial registration Registered d.d. 23-04-2020 under number ‘NL8550’ in the Dutch Trial Register: https://onderzoekmetmensen.nl/en/trial/23075
- Published
- 2024
- Full Text
- View/download PDF
42. Understanding reliability of the observer-reported communication ability measure within Angelman syndrome through the lens of generalizability theory.
- Author
-
Chen, Dandan, Zigler, Christina K., Lin, Li, Lucas, Nicole, McFatrich, Molly, Panagoulias, Jennifer, Berent, Allyson, and Reeve, Bryce B.
- Subjects
RESEARCH funding ,CRONBACH'S alpha ,ANGELMAN syndrome ,RESEARCH evaluation ,STATISTICAL sampling ,DECISION making ,DESCRIPTIVE statistics ,MAXIMUM likelihood statistics ,COMMUNICATION ,MEASUREMENT errors ,STATISTICAL reliability ,THEORY ,CONFIDENCE intervals ,ACCURACY ,RELIABILITY (Personality trait) ,GENOTYPES ,PATIENT aftercare - Abstract
Aims: Caregivers rate improved communication ability as one of the most desired outcomes for successful interventions for individuals with Angelman syndrome (AS). When measuring communication ability in clinical trials, the reliability of such measures is critical for detecting significant changes over time. This study examined the reliability of the Observed-Reported Communication Ability (ORCA) measure completed by caregivers of individuals with AS. Methods: The ORCA measure was completed by 249 caregivers with 170 caregivers completing the ORCA measure again after 5–12 days. Generalizability theory was used to examine the following sources of measurement error in ORCA scores: concepts, subdomains, assessment points, and the interactions among those facets and the object of measurement: communication ability. Three generalizability studies were conducted to understand the reliability of the ORCA measure for different measurement designs. Decision studies were carried out to demonstrate the optimization of measurement procedures of the ORCA measure. Results: G and Phi coefficients of the original measurement design exceeded the 0.80 threshold considered sufficiently reliable to make relative and absolute decisions about the communication ability of individuals with AS based on their caregivers' observed scores. The optimization procedures indicated that increasing the number of communication concepts and/or assessment points leads to more reliable estimates of communication. Conclusion: The ORCA measure was able to reliably distinguish different levels of communication ability among individuals with AS. Multiple assessment points and or more concepts would provide more precise estimates of an individual's communication ability but at the cost of survey fatigue. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
43. Specificity of Early Childhood Hyperphagia Profiles in Neurogenetic Conditions.
- Author
-
Andrews, Sara M., Panjwani, Anita A., Potter, Sarah Nelson, Hamrick, Lisa R., Wheeler, Anne C., and Kelleher, Bridgette L.
- Subjects
HYPERPHAGIA ,PRADER-Willi syndrome ,WILLIAMS syndrome ,ANGELMAN syndrome ,EXTERNALIZING behavior - Abstract
Hyperphagia is highly penetrant in Prader-Willi syndrome (PWS) and has increasingly been reported in other neurogenetic conditions (NGC). The Hyperphagia Questionnaire (HQ) was completed by caregivers of 4–8-year-olds with PWS (n = 17), Angelman syndrome (AS; n = 22), Williams syndrome (WS; n = 25), or low-risk controls (LRC; n = 35). All NGC groups were significantly elevated in HQ Total and Behavior scores compared to LRC. Only AS and WS were significantly elevated in the Drive domain, and only PWS in the Severity domain. After controlling for externalizing behavior, HQ Total scores were higher for PWS relative to other groups. Hyperphagic symptoms may not differentiate PWS from other NGCs in early childhood. However, hyperphagic phenotypes may be most severe in PWS. Further investigation of these profiles may inform etiology and syndrome-specific treatments. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
44. The Type, Severity, and Impact of Sleep Problems in Children With Angelman Syndrome and Parental Help-seeking Patterns.
- Author
-
McLay, Laurie K., Hansen, Sarah G., Blampied, Neville M., France, Karyn G., and Rispoli, Mandy
- Subjects
SLEEP ,ANGELMAN syndrome ,BEDTIME ,HELP-seeking behavior ,SYNDROMES in children ,DEVELOPMENTAL disabilities - Abstract
Angelman syndrome (AS) is a rare genetic developmental disability that presents with high rates of co-occurring sleep difficulties. Most existing research has focused on the pathophysiology of sleep problems in people with AS, and suggests that sleep problems are the result of genetic and neurobiological factors. However, little is known about the role of the social environment and learning in sleep problems in children with AS. This descriptive study used survey data from 139 parents of children with AS to investigate: 1) the type, topography and severity of children's sleep problems; 2) the collateral child, parent and family impacts of the sleep problems; 3) treatment selection practices and the perceived effectiveness of these treatments; and 4) sources of support and treatment advice received. Parents reported that the majority of children experienced sleep problems, resulting in numerous deleterious effects on child and family functioning. They also reported high levels of concern about these sleep problems, but low levels of perceived support. Study findings highlight the need to establish a disability-specific profile of the type and impact of sleep problems experienced by children with AS, and have further implications for the delivery of clinical services and support provided to parents of children with AS. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
45. Undiagnosed rare disease clinic identifies a novel UBE3A variant in two sisters with Angelman syndrome: The end of a diagnostic odyssey.
- Author
-
Bruns, Rebecca, Liaqat, Khurram, Nasir, Abdul, Treat, Kayla, Murthy, Vinaya S., Mantcheva, Lili, Torres, Wilfredo, Conboy, Erin, and Vetrini, Francesco
- Subjects
ANGELMAN syndrome ,RARE diseases ,DISABILITIES ,UBIQUITIN ligases ,DEVELOPMENTAL delay ,MOVEMENT disorders - Abstract
Angelman syndrome (AS, MIM #105830) is a neurodevelopmental disorder characterized by severe intellectual disability, profound developmental delay, movement or balance problems, an excessively cheerful disposition, and seizures. AS results from inadequate expression of the maternal UBE3A gene (MIM #601623), which encodes an E3 ligase in the ubiquitin‐proteasome pathway. Here we present the case of two sisters with features consistent with AS who had negative methylation analyses. An autism/intellectual disability expanded panel revealed a maternally inherited novel UBE3A (NM_001354506.2) variant c.2443C>T p.(Pro815Ser) in both patients that was initially classified as a variant of uncertain significance. The patients were enrolled in Indiana University's Undiagnosed Rare Disease Clinic (URDC) to further investigate the variant. Additional data, including deep phenotyping, familial segregation analysis, and in silico studies, suggest that the variant is likely pathogenic. 3D modeling studies based on the available crystal structure revealed that the Pro815Ser variant can introduce more flexibility into the protein and alter its enzymatic activity. Recent literature confirms the pathogenic nature of the variant. Reanalysis of the UBE3A variant has heightened existing knowledge of AS and has offered this family an end to their diagnostic odyssey. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
46. Establishing a Standardized DNA Extraction Method Using NaCl from Oral Mucosa Cells for Its Application in Imprinting Diseases Such as Prader–Willi and Angelman Syndromes: A Preliminary Investigation.
- Author
-
da Fonseca, Letícia Lopes Cabral Guimarães, Rocha, Danielle Nascimento, Cintra, Hiago Azevedo, de Araújo, Luiza Loureiro, dos Santos, Gabrielle Leal Monteiro, de Faria, Leonardo Lima, Salú, Margarida dos Santos, Leite, Silvia Helena dos Santos, Rocha, Adriana Duarte, Lopes, Maria da Conceição Borges, Ferreira, Igor Ribeiro, Gomes, Leonardo Henrique Ferreira, and Guida, Letícia Cunha
- Subjects
PRADER-Willi syndrome ,NUCLEIC acid isolation methods ,ORAL mucosa ,ANGELMAN syndrome ,DNA analysis ,SALT - Abstract
Background: Diagnosing imprinting defects in neonates and young children presents challenges, often necessitating molecular analysis for a conclusive diagnosis. The isolation of genetic material from oral swabs becomes crucial, especially in settings where blood sample collection is impractical or for vulnerable populations like newborns, who possess limited blood volumes and are often too fragile for invasive procedures. Oral swab samples emerge as an excellent source of DNA, effectively overcoming obstacles associated with rare diseases. Methods: In our study, we specifically addressed the determination of the quality and quantity of DNA extracted from oral swab samples using NaCl procedures. Results: We compared these results with extractions performed using a commercial kit. Subsequently, the obtained material underwent MS–HRM analysis for loci associated with imprinting diseases such as Prader–Willi and Angelman syndromes. Conclusions: Our study emphasizes the significance of oral swab samples as a reliable source for obtaining DNA for MS–HRM analysis. NaCl extraction stands out as a practical and cost-effective method for genetic studies, contributing to a molecular diagnosis that proves particularly beneficial for patients facing delays in characterization, ultimately influencing their treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
47. Exploring an objective measure of overactivity in children with rare genetic syndromes.
- Author
-
O'Sullivan, Rory, Bissell, Stacey, Agar, Georgie, Spiller, Jayne, Surtees, Andrew, Heald, Mary, Clarkson, Emma, Khan, Aamina, Oliver, Christopher, Bagshaw, Andrew P., and Richards, Caroline
- Subjects
HYPERKINESIA ,TUBEROUS sclerosis ,ANGELMAN syndrome ,INTELLECTUAL disabilities ,ATTENTION-deficit hyperactivity disorder ,SYNDROMES - Abstract
Background: Overactivity is prevalent in several rare genetic neurodevelopmental syndromes, including Smith-Magenis syndrome, Angelman syndrome, and tuberous sclerosis complex, although has been predominantly assessed using questionnaire techniques. Threats to the precision and validity of questionnaire data may undermine existing insights into this behaviour. Previous research indicates objective measures, namely actigraphy, can effectively differentiate non-overactive children from those with attention-deficit hyperactivity disorder. This study is the first to examine the sensitivity of actigraphy to overactivity across rare genetic syndromes associated with intellectual disability, through comparisons with typically-developing peers and questionnaire overactivity estimates. Methods: A secondary analysis of actigraphy data and overactivity estimates from The Activity Questionnaire (TAQ) was conducted for children aged 4-15 years with Smith-Magenis syndrome (N=20), Angelman syndrome (N=26), tuberous sclerosis complex (N=16), and typically-developing children (N=61). Actigraphy data were summarized using the M10 non-parametric circadian rhythm variable, and 24-hour activity profiles were modelled via functional linear modelling. Associations between actigraphy data and TAQ overactivity estimates were explored. Differences in actigraphy-defined activity were also examined between syndrome and typically-developing groups, and between children with high and low TAQ overactivity scores within syndromes. Results: M10 and TAQ overactivity scores were strongly positively correlated for children with Angelman syndrome and Smith-Magenis syndrome. M10 did not substantially differ between the syndrome and typically-developing groups. Higher early morning activity and lower evening activity was observed across all syndrome groups relative to typically-developing peers. High and low TAQ group comparisons revealed syndrome-specific profiles of overactivity, persisting throughout the day in Angelman syndrome, occurring during the early morning and early afternoon in Smith-Magenis syndrome, and manifesting briefly in the evening in tuberous sclerosis complex. Discussion: These findings provide some support for the sensitivity of actigraphy to overactivity in children with rare genetic syndromes, and offer syndrome-specific temporal descriptions of overactivity. The findings advance existing descriptions of overactivity, provided by questionnaire techniques, in children with rare genetic syndromes and have implications for the measurement of overactivity. Future studies should examine the impact of syndrome-related characteristics on actigraphy-defined activity and overactivity estimates from actigraphy and questionnaire techniques. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
48. Sleep disturbance in Angelman syndrome patients.
- Author
-
Qu, Song, Wang, Junyi, Guan, Xingying, Song, Cui, and Wang, Yanyan
- Subjects
SLEEP interruptions ,ANGELMAN syndrome ,SOMNOLOGY ,DROWSINESS ,BEHAVIOR therapy ,SLEEP disorders - Abstract
Angelman syndrome (AS) is a neurodevelopmental disorder caused by abnormal expression of the maternal ubiquitin protein ligase E3A gene (UBE3A). As one of the most challenging symptoms and important focuses of new treatment, sleep disturbance is reported to occur in 70–80% of patients with AS and has a serious impact on the lives of patients and their families. Although clinical studies and animal model studies have provided some clues, recent research into sleep disorders in the context of AS is still very limited. It is generally accepted that there is an interaction between neurodevelopment and sleep; however, there is no recognized mechanism for sleep disorders in AS patients. Accordingly, there are no aetiologically specific clinical treatments for AS-related sleep disorders. The most common approaches involve ameliorating symptoms through methods such as behavioural therapy and symptomatic pharmacotherapy. In recent years, preclinical and clinical studies on the targeted treatment of AS have emerged. Although precision therapy for restoring the UBE3A level and the function of its signalling pathways is inevitably hindered by many remaining obstacles, this approach has the potential to address AS-related sleep disturbance. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
49. Outcome measures in Angelman syndrome.
- Author
-
Hagenaar, Doesjka A., Bindels-de Heus, Karen G. C. B., van Gils, Maud M., van den Berg, Louise, ten Hoopen, Leontine W., Affourtit, Philine, Pel, Johan J. M., Joosten, Koen F. M., Hillegers, Manon H. J., Moll, Henriëtte A., de Wit, Marie-Claire Y., Dieleman, Gwen C., and Mous, Sabine E.
- Subjects
ANGELMAN syndrome ,NEAR infrared spectroscopy ,VISUAL perception ,WEIGHT gain ,EYE tracking - Abstract
Background: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems, emotional/behavioral challenges, and a tendency towards hyperphagia and weight gain. The characteristics of AS make it difficult to measure these children's functioning with standard clinical tests. Feasible outcome measures are needed to measure current functioning and change over time, in clinical practice and clinical trials. Aim: Our first aim is to assess the feasibility of several functional tests. We target domains of neurocognitive functioning and physical growth using the following measurement methods: eye-tracking, functional Near-Infrared Spectroscopy (fNIRS), indirect calorimetry, bio-impedance analysis (BIA), and BOD POD (air-displacement plethysmography). Our second aim is to explore the results of the above measures, in order to better understand the AS phenotype. Methods: The study sample consisted of 28 children with AS aged 2–18 years. We defined an outcome measure as feasible when (1) at least 70% of participants successfully finished the measurement and (2) at least 60% of those participants had acceptable data quality. Adaptations to the test procedure and reasons for early termination were noted. Parents rated acceptability and importance and were invited to make recommendations to increase feasibility. The results of the measures were explored. Results: Outcome measures obtained with eye-tracking and BOD POD met the definition of feasibility, while fNIRS, indirect calorimetry, and BIA did not. The most important reasons for early termination of measurements were showing signs of protest, inability to sit still and poor/no calibration (eye-tracking specific). Post-calibration was often applied to obtain valid eye-tracking results. Parents rated the BOD POD als most acceptable and fNIRS as least acceptable for their child. All outcome measures were rated to be important. Exploratory results indicated longer reaction times to high salient visual stimuli (eye-tracking) as well as high body fat percentage (BOD POD). Conclusions: Eye-tracking and BOD POD are feasible measurement methods for children with AS. Eye-tracking was successfully used to assess visual orienting functions in the current study and (with some practical adaptations) can potentially be used to assess other outcomes as well. BOD POD was successfully used to examine body composition. Trial registration: Registered d.d. 23-04-2020 under number 'NL8550' in the Dutch Trial Register: https://onderzoekmetmensen.nl/en/trial/23075 [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
50. Child characteristics associated with child quality of life and parenting stress in Angelman syndrome.
- Author
-
Hagenaar, D. A., Bindels‐de Heus, K. G. C. B., Lubbers, K., ten Hoopen, L. W., Rietman, A. B., de Nijs, P. F. A., Hillegers, M. H. J., Moll, H. A., de Wit, M. C. Y., Dieleman, G. C., and Mous, S. E.
- Subjects
HOSPITALS ,PARENTS of children with disabilities ,ANGELMAN syndrome ,AGE distribution ,REGRESSION analysis ,BEHAVIOR disorders in children ,SLEEP disorders ,CHILD Behavior Checklist ,PSYCHOSOCIAL factors ,QUALITY of life ,AFFECTIVE disorders ,GENOTYPES ,QUESTIONNAIRES ,RESEARCH funding ,PSYCHOLOGICAL stress ,LONGITUDINAL method ,MENTAL illness ,SYMPTOMS ,DISEASE complications ,CHILDREN - Abstract
Background: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterised by severe intellectual disability, movement disorder, epilepsy, sleeping problems, and behavioural issues. Little is known on child health‐related quality of life (HRQoL) in AS. AS family studies have reported elevated parenting stress and a high impact of the child's syndrome on the parent. It is unclear which factors influence child HRQoL and parenting stress/impact in AS. Methods: We collected data prospectively through standardised clinical assessments of children with AS at the ENCORE Expertise centre for Angelman Syndrome at the Erasmus MC Sophia Children's Hospital. A linear regression analysis was conducted for the following outcome variables: (1) child HRQoL (Infant and Toddler Quality of Life Questionnaire); (2) the impact of the child's syndrome on the parent (Infant and Toddler Quality of Life Questionnaire); and (3) parenting stress (Parenting Stress Index). Predictor variables were child genotype, epilepsy, sleeping problems (Sleep Disturbance Scale for Children), cognitive developmental level (Bayley Cognition Scale), autistic features (Autism Diagnostic Observation Schedule) and emotional/behavioural problems (Child Behaviour Checklist). Covariates were sex, age and socio‐economic status. Results: The study sample consisted of 73 children with AS, mean age = 9.1 years, range = 2–18 years. Emotional/behavioural problems were the strongest significant predictor of lowered child HRQoL. Internalising problems were driving this effect. In addition, having the deletion genotype and higher age was related to lower child HRQoL. Sleeping problems were related to a higher impact of the child's syndrome on the parent. Finally, emotional/behavioural problems were associated with higher parenting stress. Cognitive developmental level, autistic features and epilepsy were not a significant predictor of child HRQoL and parenting stress/impact. Conclusions: These results suggest that interventions aimed at increasing child HRQoL and decreasing parenting stress/impact in AS should focus on child emotional/behavioural problems and sleeping problems, using a family‐centred approach. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
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