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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 -
International Journal of Neonatal... Jun 2024Duchenne muscular dystrophy (DMD) is an X-linked progressive disorder and the most common type of muscular dystrophy in children. As newborn screening (NBS) for DMD...
Age-Related Blood Levels of Creatine Kinase-MM in Newborns and Patients with Duchenne Muscular Dystrophy: Considerations for the Development of Newborn Screening Algorithms.
Duchenne muscular dystrophy (DMD) is an X-linked progressive disorder and the most common type of muscular dystrophy in children. As newborn screening (NBS) for DMD undergoes evaluation for the Recommended Uniform Screening Panel and is already mandated in multiple states, refining NBS algorithms is of utmost importance. NBS for DMD involves measuring creatine kinase-MM (CK-MM) concentration-a biomarker of muscle damage-in dried blood spots. The current test is FDA-approved for samples obtained less than 72 h after birth. Separate reference ranges are needed for samples collected later than 72 h after birth. In this study, we investigated the relationship between age and CK-MM in presumed healthy newborns to inform NBS algorithm designs. In patients with DMD, CK-MM is persistently elevated in childhood and adolescence, while it may be transiently elevated for other reasons in healthy newborns. CK-MM decrease over time was demonstrated by a population sample of 20,306 presumed healthy newborns tested between 0 and 60 days of life and repeat testing of 53 newborns on two separate days. In the population sample, CK-MM concentration was highest in the second 12 h period of life (median = 318 ng/mL) when only 57.6% of newborns tested below 360 ng/mL, the lowest previously published cutoff. By 72 h of age, median CK-MM concentration was 97 ng/mL, and 96.0% of infants had concentrations below 360 ng/mL. Between 72 h and 60 days, median CK-MM concentration ranged from 32 to 37 ng/mL. Establishing age-related cutoffs is crucial for optimizing the sensitivity and specificity of NBS for DMD.
PubMed: 38920848
DOI: 10.3390/ijns10020041 -
BioRxiv : the Preprint Server For... Jun 2024Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder with profoundly debilitating symptoms with no FDA-approved cure or therapeutic. Brain-derived...
Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder with profoundly debilitating symptoms with no FDA-approved cure or therapeutic. Brain-derived neurotrophic factor (BDNF), and its receptor TrkB, have a well-established role as regulators of synaptic plasticity, dendritic outgrowth, dendritic spine formation and maintenance. Previously, we reported that the association of PSD-95 with TrkB is critical for intact BDNF signaling in the AS mouse model, as illustrated by attenuated PLCγ and PI3K signaling and intact MAPK pathway signaling. These data suggest that drugs tailored to enhance the TrkB-PSD-95 interaction may provide a novel approach for the treatment of AS and a variety of NDDs. To evaluate this critical interaction, we synthesized a class of high-affinity PSD-95 ligands that bind specifically to the PDZ3 domain of PSD-95, denoted as Syn3 peptidomimetic ligands. We evaluated Syn3 and its analog D-Syn3 (engineered using dextrorotary (D)-amino acids) using the exon 2 deletion mouse model of AS. Following systemic administration of Syn3 and D-Syn3, we demonstrated improvement in the seizure domain of AS. Learning and memory using the novel object recognition assay also illustrated improved cognition following Syn3 and D-Syn3, along with restored long-term potentiation. Finally, D-Syn3 treated mice showed a partial rescue in motor learning. Neither Syn3 nor D-Syn3 improved gross exploratory locomotion deficits, nor gait impairments that have been well documented in the AS rodent models. These findings highlight the need for further investigation of this compound class as a potential therapeutic for AS and other genetic NDDs.
PubMed: 38895218
DOI: 10.1101/2024.06.07.597833 -
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 -
Frontiers in Neuroanatomy 2024Angelman syndrome (AS) is a neurogenetic disorder caused by mutations or deletions in the maternally-inherited allele, leading to a loss of UBE3A protein expression in...
Angelman syndrome (AS) is a neurogenetic disorder caused by mutations or deletions in the maternally-inherited allele, leading to a loss of UBE3A protein expression in neurons. The paternally-inherited allele is epigenetically silenced in neurons during development by a noncoding transcript (). 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 -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 biology with greater relevance to human neurodevelopmental contexts, we investigated UBE3A and 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 hybridization, we mapped UBE3A and 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 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 linked to AS.
PubMed: 38873093
DOI: 10.3389/fnana.2024.1410791 -
Stem Cell Research Aug 2024The neurodevelopmental disorder Angelman syndrome (AS) has an incidence of 1:15.000 live births and is caused by absence of UBE3A protein, showing imprinted gene...
The neurodevelopmental disorder Angelman syndrome (AS) has an incidence of 1:15.000 live births and is caused by absence of UBE3A protein, showing imprinted gene expression in the brain. Imprinted genes are controlled by differentially methylated regions resulting in parent-of-origin dependent gene expression. Two iPS cell lines derived from patients with AS and one healthy control iPSC line were used to integrate a 3rd generation reverse tetracycline transactivator protein (rtTA3) into the AAVS1 locus on chromosome 19. The rtTA allows tetracycline-dependent activation of an inducible promoter that can be introduced at a position of interest in the cell lines described here.
Topics: Induced Pluripotent Stem Cells; Angelman Syndrome; Humans; Cell Line
PubMed: 38843694
DOI: 10.1016/j.scr.2024.103454 -
Epilepsia Open Jun 2024Chromosomal abnormalities are associated with a broad spectrum of clinical manifestations, one of the more commonly observed of which is epilepsy. The frequency,... (Review)
Review
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.
PubMed: 38837855
DOI: 10.1002/epi4.12951 -
Therapeutic Advances in Rare Disease 2024Angelman syndrome (AS) and duplication 15q (dup15q) syndrome are rare neurogenetic conditions arising from a common locus on the long arm of chromosome 15. Individuals... (Review)
Review
Linking Angelman and dup15q data for expanded research (LADDER) database: a model for advancing research, clinical guidance, and therapeutic development for rare conditions.
Angelman syndrome (AS) and duplication 15q (dup15q) syndrome are rare neurogenetic conditions arising from a common locus on the long arm of chromosome 15. Individuals with both conditions share some clinical features (e.g. intellectual disability, epilepsy) and often require lifelong care. Disease-modifying therapies for both conditions are emerging, resulting in a significant need for a better understanding of the natural history of both AS and dup15q. Patient advocacy groups for both conditions recognized a need for a data repository that would link data on individuals from multiple sources to expand research, increase understanding of natural history, and accelerate the development of treatments, resulting in the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database. This paper describes the development and functionality of the LADDER Database - including challenges, lessons learned, and preliminary feasibility - and how it can be used as a model for other rare conditions.
PubMed: 38808315
DOI: 10.1177/26330040241254122 -
Genes May 2024Diagnosing imprinting defects in neonates and young children presents challenges, often necessitating molecular analysis for a conclusive diagnosis. The isolation of...
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.
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.
Topics: Humans; Mouth Mucosa; Angelman Syndrome; Prader-Willi Syndrome; DNA; Genomic Imprinting; Sodium Chloride; Infant, Newborn; Male; Imprinting Disorders
PubMed: 38790270
DOI: 10.3390/genes15050641 -
Journal of Patient-reported Outcomes May 2024Caregivers rate improved communication ability as one of the most desired outcomes for successful interventions for individuals with Angelman syndrome (AS). When...
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.
Topics: Humans; Angelman Syndrome; Caregivers; Reproducibility of Results; Communication; Male; Female; Child; Adult; Adolescent; Child, Preschool; Psychometrics; Surveys and Questionnaires; Young Adult
PubMed: 38743304
DOI: 10.1186/s41687-024-00725-9