-
Journal of Intellectual Disability... Nov 2022Angelman syndrome (AS) is a neurogenetic disorder that causes severe intellectual disability, expressive language deficits, motor impairment, ataxia, sleep problems,...
BACKGROUND
Angelman syndrome (AS) is a neurogenetic disorder that causes severe intellectual disability, expressive language deficits, motor impairment, ataxia, sleep problems, epileptic seizures and a happy disposition. People with AS frequently experience gastrointestinal (GI) symptoms.
METHOD
This study used data from the Global Angelman Syndrome Registry to explore the relationship between early and current GI symptoms and co-morbidity in children and adolescents with AS (n = 173). Two groups that experienced a high (n = 91) and a low (n = 82) frequency of GI symptoms were examined in relation to feeding and GI history in infancy, sleep and toileting problems, levels of language and communication and challenging behaviours. Predictors of GI symptoms were then investigated using a series of logistic regressions.
RESULTS
This analysis found that constipation and gastroesophageal reflux affected 84% and 64%, of the sample, respectively. The high frequency of GI symptoms were significantly associated with: 'refusal to nurse', 'vomiting', 'arching', 'difficulty gaining weight', gastroesophageal reflux, 'solid food transition', frequency of night-time urinary continence and sleep hyperhidrosis during infancy. GI symptoms were not significantly associated with sleep, toileting, language or challenging behaviours. Significant predictors of high frequency GI symptoms were gastroesophageal reflux and sleep hyperhidrosis.
CONCLUSIONS
Future research needs to investigate the association between AS and GI co-morbidity in adults with AS.
Topics: Adolescent; Adult; Angelman Syndrome; Child; Gastroesophageal Reflux; Gastrointestinal Diseases; Humans; Hyperhidrosis; Morbidity
PubMed: 36052644
DOI: 10.1111/jir.12975 -
Journal of Applied Genetics May 2023Autism spectrum disorder (ASD) is a heterogeneous group of early-onset neurodevelopmental disorders known to be highly heritable with a complex genetic architecture.... (Review)
Review
Autism spectrum disorder (ASD) is a heterogeneous group of early-onset neurodevelopmental disorders known to be highly heritable with a complex genetic architecture. Abnormal brain developmental trajectories that impact synaptic functioning, excitation-inhibition balance and brain connectivity are now understood to play a central role in ASD. Ongoing efforts to identify the genetic underpinnings still prove challenging, in part due to phenotypic and genetic heterogeneity.This review focuses on parent-of-origin effects (POEs), where the phenotypic effect of an allele depends on its parental origin. POEs include genomic imprinting, transgenerational effects, mitochondrial DNA, sex chromosomes and mutational transmission bias. The motivation for investigating these mechanisms in ASD has been driven by their known impacts on early brain development and brain functioning, in particular for the most well-documented POE, genomic imprinting. Moreover, imprinting is implicated in syndromes such as Angelman and Prader-Willi, which frequently share comorbid symptoms with ASD. In addition to other regions in the genome, this comprehensive review highlights the 15q11-q13 and 7q chromosomal regions as well as the mitochondrial DNA as harbouring the majority of currently identified POEs in ASD.
Topics: Humans; Autism Spectrum Disorder; Prader-Willi Syndrome; Angelman Syndrome; Brain; Genomic Imprinting; DNA, Mitochondrial
PubMed: 36710277
DOI: 10.1007/s13353-022-00742-8 -
Brain Communications 2022Angelman syndrome is a neurodevelopmental disorder caused by deficiency of the maternally inherited gene in neurons. Antisense oligonucleotide therapies are under...
Angelman syndrome is a neurodevelopmental disorder caused by deficiency of the maternally inherited gene in neurons. Antisense oligonucleotide therapies are under development to reinstate UBE3A protein production. Non-invasive biomarkers to detect target engagement and treatment response are needed to support clinical trials. Delta power measured in the scalp EEG is a reliable biomarker for Angelman syndrome but varies widely across individuals and throughout development, making detection of a treatment effect using single measurements challenging. We utilized a longitudinal dataset of 204 EEG recordings from 56 subjects with Angelman syndrome to develop a natural history model of delta (2-4 Hz) power, with predictors of age, elapsed time, and relative delta power at an initial recording. Using this model, we computed the sample and effect sizes needed to detect a treatment effect in a human clinical trial with 80% power. We applied the same model structure to a mouse model of Angelman syndrome ( = 41) to detect antisense oligonucleotide-mediated treatment effects on absolute delta activity and expression. In humans, delta power at a second time point can be reliably predicted using the natural history model. In mice, a treatment effect can be detected after antisense oligonucleotide treatment targeting the antisense transcript through at least 8 weeks post-treatment ( < 1e-15). Deviations in delta power from the expected natural history correlated with expression in the mouse model ( < 0.001). Deviations in delta power from a human natural history model in Angelman syndrome can detect antisense oligonucleotide-mediated improvement in expression in Angelman syndrome mice and may be relevant for human clinical trials.
PubMed: 35611307
DOI: 10.1093/braincomms/fcac106 -
Cells Nov 2020Protein ubiquitination belongs to the best characterized pathways of protein degradation in the cell; however, our current knowledge on its physiological consequences is... (Review)
Review
Protein ubiquitination belongs to the best characterized pathways of protein degradation in the cell; however, our current knowledge on its physiological consequences is just the tip of an iceberg. The divergence of enzymatic executors of ubiquitination led to some 600-700 E3 ubiquitin ligases embedded in the human genome. Notably, mutations in around 13% of these genes are causative of severe neurological diseases. Despite this, molecular and cellular context of ubiquitination remains poorly characterized, especially in the developing brain. In this review article, we summarize recent findings on brain-expressed HECT-type E3 UBE3 ligases and their murine orthologues, comprising Angelman syndrome UBE3A, Kaufman oculocerebrofacial syndrome UBE3B and autism spectrum disorder-associated UBE3C. We summarize evolutionary emergence of three genes, the biochemistry of UBE3 enzymes, their biology and clinical relevance in brain disorders. Particularly, we highlight that uninterrupted action of UBE3 ligases is a sine qua non for cortical circuit assembly and higher cognitive functions of the neocortex.
Topics: Amino Acid Sequence; Evolution, Molecular; Humans; Ubiquitin-Protein Ligases
PubMed: 33182779
DOI: 10.3390/cells9112455 -
Molecular Autism Jan 2023Phenotypic studies have identified distinct patterns of autistic characteristics in genetic syndromes associated with intellectual disability (ID), leading to diagnostic...
BACKGROUND
Phenotypic studies have identified distinct patterns of autistic characteristics in genetic syndromes associated with intellectual disability (ID), leading to diagnostic uncertainty and compromised access to autism-related support. Previous research has tended to include small samples and diverse measures, which limits the generalisability of findings. In this study, we generated detailed profiles of autistic characteristics in a large sample of > 1500 individuals with rare genetic syndromes.
METHODS
Profiles of autistic characteristics based on the Social Communication Questionnaire (SCQ) scores were generated for thirteen genetic syndrome groups (Angelman n = 154, Cri du Chat n = 75, Cornelia de Lange n = 199, fragile X n = 297, Prader-Willi n = 278, Lowe n = 89, Smith-Magenis n = 54, Down n = 135, Sotos n = 40, Rubinstein-Taybi n = 102, 1p36 deletion n = 41, tuberous sclerosis complex n = 83 and Phelan-McDermid n = 35 syndromes). It was hypothesised that each syndrome group would evidence a degree of specificity in autistic characteristics. To test this hypothesis, a classification algorithm via support vector machine (SVM) learning was applied to scores from over 1500 individuals diagnosed with one of the thirteen genetic syndromes and autistic individuals who did not have a known genetic syndrome (ASD; n = 254). Self-help skills were included as an additional predictor.
RESULTS
Genetic syndromes were associated with different but overlapping autism-related profiles, indicated by the substantial accuracy of the entire, multiclass SVM model (55% correctly classified individuals). Syndrome groups such as Angelman, fragile X, Prader-Willi, Rubinstein-Taybi and Cornelia de Lange showed greater phenotypic specificity than groups such as Cri du Chat, Lowe, Smith-Magenis, tuberous sclerosis complex, Sotos and Phelan-McDermid. The inclusion of the ASD reference group and self-help skills did not change the model accuracy.
LIMITATIONS
The key limitations of our study include a cross-sectional design, reliance on a screening tool which focuses primarily on social communication skills and imbalanced sample size across syndrome groups.
CONCLUSIONS
These findings replicate and extend previous work, demonstrating syndrome-specific profiles of autistic characteristics in people with genetic syndromes compared to autistic individuals without a genetic syndrome. This work calls for greater precision of assessment of autistic characteristics in individuals with genetic syndromes associated with ID.
Topics: Humans; Autistic Disorder; Tuberous Sclerosis; Cross-Sectional Studies; Intellectual Disability; Syndrome
PubMed: 36639821
DOI: 10.1186/s13229-022-00530-5 -
Developmental Medicine and Child... Jul 2021Half a century ago, Harry Angelman reported three patients with overlapping clinical features, now well known as Angelman syndrome. Angelman syndrome is caused by... (Review)
Review
Half a century ago, Harry Angelman reported three patients with overlapping clinical features, now well known as Angelman syndrome. Angelman syndrome is caused by mutations affecting the maternally inherited UBE3A gene, which encodes an E3-ubiquitin ligase that is critical for typical postnatal brain development. Emerging evidence indicates that UBE3A plays a particularly important role in the nucleus. However, the critical substrates that are controlled by UBE3A remain elusive, which hinders the search for effective treatments. Moreover, given the multitude of signalling mechanisms that are derailed, it is unlikely that targeting a single pathway is going to be very effective. Therefore, expectations are very high for approaches that aim to restore UBE3A protein levels. A particular promising strategy is an antisense oligonucleotide approach, which activates the silenced paternal UBE3A gene. When successful, such treatments potentially offer a disease-modifying therapy for Angelman syndrome and several other neurodevelopmental disorders. What this paper adds Loss of UBE3A affects multiple signalling pathways in the brain. Emerging evidence suggests that UBE3A plays a critical role in the cell nucleus. Trials using antisense oligonucleotides to restore UBE3A levels are continuing.
Topics: Angelman Syndrome; Animals; Disease Models, Animal; Humans; Mice; Oligonucleotides, Antisense; Ubiquitin-Protein Ligases
PubMed: 33543479
DOI: 10.1111/dmcn.14831 -
Research Square Jul 2023Angelman syndrome (AS) is a rare neurogenetic disorder characterized by developmental delays, speech impairments, ataxic movements, and in some cases, hyperphagic...
Angelman syndrome (AS) is a rare neurogenetic disorder characterized by developmental delays, speech impairments, ataxic movements, and in some cases, hyperphagic feeding behavior. Loss of function mutations, loss of expression from the maternal allele or absence of maternal UBE3A result in AS. Recent studies have established a connection between and the mechanosensitive ion channel , suggesting the potential role of UBE3A in the regulation of PIEZO channels. In this study, we investigated the role of () in associated hyperphagic feeding behavior. We developed a novel assay using green fluorescent protein (GFP) expressing yeast to quantify gut distention in flies with and mutations. We confirmed that loss of function flies displayed gut distention to almost identical levels as flies. Further analysis using deficiency (Df) lines encompassing the locus provided proof for a role of in satiety signaling. We also investigated endogenous expression across the fly midgut and tracheal system. Piezo protein could be detected in both neurons and trachea of the midgut. Overexpression of driven by the promoter resulted in distinct tracheal remodeling within the midgut. These findings suggest that plays a key role in the regulation of Piezo and that subsequent dysregulation of these ion channels may explain the hyperphagic behavior observed in 32% of cases of AS. Further investigation will be needed to identify the intermediate protein(s) interacting between the Dube3a ubiquitin ligase and Piezo channels, as Piezo does not appear to be a direct ubiquitin substrate for UBE3A in mice and humans.
PubMed: 37461494
DOI: 10.21203/rs.3.rs-3101314/v1 -
Multiple Sclerosis (Houndmills,... Aug 2023Demographic characteristics, social determinants of health (SDoH), health inequities, and health disparities substantially influence the general and disease-specific... (Review)
Review
BACKGROUND
Demographic characteristics, social determinants of health (SDoH), health inequities, and health disparities substantially influence the general and disease-specific health outcomes of people with multiple sclerosis (MS). Participants in clinical trials do not represent all people with MS treated in practice.
OBJECTIVE
To provide recommendations for enhancing diversity and inclusion in clinical trials in MS.
METHODS
We held an international workshop under the Auspices of the International Advisory Committee on Clinical Trials in MS (the "Committee") to develop recommendations regarding diversity and inclusivity of participants of clinical trials in MS. Workshop attendees included members of the Committee as well as external participants. External participants were selected based on expertise in trials, SDoH, health equity and regulatory science, and diversity with respect to gender, race, ethnicity, and geography.
RESULTS
Recommendations include use of diversity plans, community engagement and education, cultural competency training, biologically justified rather than templated eligibility criteria, adaptive designs that allow broadening of eligibility criteria over the course of a trial, and logistical and practical adjustments to reduce study participant burden. Investigators should report demographic and SDoH characteristics of participants.
CONCLUSION
These recommendations provide sponsors and investigators with methods of improving diversity and inclusivity of clinical trial populations in MS.
Topics: Humans; Ethnicity; Multiple Sclerosis; Research Design; Surveys and Questionnaires; Clinical Trials as Topic
PubMed: 37555490
DOI: 10.1177/13524585231189677 -
Autism Research : Official Journal of... May 2022Angelman syndrome (AS) is a genetic neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, hypotonia, and...
Angelman syndrome (AS) is a genetic neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, hypotonia, and motor coordination deficits. Motor abilities are an important outcome measure in AS as they comprise a broad repertoire of metrics including ataxia, hypotonia, delayed ambulation, crouched gait, and poor posture, and motor dysfunction affects nearly every individual with AS. Guided by collaborative work with AS clinicians studying gait, the goal of this study was to perform an in-depth gait analysis using the automated treadmill assay, DigiGait. Our hypothesis is that gait presents a strong opportunity for a reliable, quantitative, and translational metric that can serve to evaluate novel pharmacological, dietary, and genetic therapies. In this study, we used an automated gait analysis system, in addition to standard motor behavioral assays, to evaluate components of motor, exploration, coordination, balance, and gait impairments across the lifespan in an AS mouse model. Our study demonstrated marked global motoric deficits in AS mice, corroborating previous reports. Uniquely, this is the first report of nuanced aberrations in quantitative spatial and temporal components of gait in AS mice compared to sex- and age-matched wildtype littermates followed longitudinally using metrics that are analogous in AS individuals. Our findings contribute evidence toward the use of nuanced motor outcomes (i.e., gait) as valuable and translationally powerful metrics for therapeutic development for AS, as well as other genetic neurodevelopmental syndromes. LAY SUMMARY: Movement disorders affect nearly every individual with Angelman Syndrome (AS). The most common motor problems include spasticity, ataxia of gait (observed in the majority of ambulatory individuals), tremor, and muscle weakness. This report focused on quantifying various spatial and temporal aspects of gait as a reliable, translatable outcome measure in a preclinical AS model longitudinally across development. By increasing the number of translational, reliable, functional outcome measures in our wheelhouse, we will create more opportunities for identifying and advancing successful medical interventions.
Topics: Angelman Syndrome; Animals; Autism Spectrum Disorder; Disease Models, Animal; Gait; Humans; Mice; Movement Disorders; Muscle Hypotonia; Outcome Assessment, Health Care
PubMed: 35274462
DOI: 10.1002/aur.2697 -
Medicina (Kaunas, Lithuania) May 2021We report the second case, to the best of our knowledge, of a mother with Prader-Willi syndrome (PWS) who gave birth to a daughter with Angelman syndrome (AS). The...
We report the second case, to the best of our knowledge, of a mother with Prader-Willi syndrome (PWS) who gave birth to a daughter with Angelman syndrome (AS). The menarche occurred when she was 16, and the following menstrual cycles were irregular, but she never took sexual hormone replacement therapy. At the age of 26, our patient with PWS became pregnant. The diagnosis was confirmed by molecular genetic testing that revealed a ~5.7 Mb deletion in the 15q11.1-15q13 region on the paternal allele in the mother with PWS and the maternal one in the daughter with AS, respectively. Both the mother with PWS and the daughter with AS showed peculiar clinical and genetic features of the two syndromes. Our case report reaffirms the possible fertility in PWS; therefore, it is very important to develop appropriate socio-sexual education programs and fertility assessments in order to guarantee the expression of a healthy sexuality.
Topics: Angelman Syndrome; Female; Fertility; Humans; Prader-Willi Syndrome; Pregnancy
PubMed: 34066798
DOI: 10.3390/medicina57050460