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Open Biology Sep 2020Prader-Willi syndrome (PWS) is caused by the loss of function of the paternally inherited 15q11-q13 locus. This region is governed by genomic imprinting, a phenomenon in... (Review)
Review
Prader-Willi syndrome (PWS) is caused by the loss of function of the paternally inherited 15q11-q13 locus. This region is governed by genomic imprinting, a phenomenon in which genes are expressed exclusively from one parental allele. The genomic imprinting of the 15q11-q13 locus is established in the germline and is largely controlled by a bipartite imprinting centre. One part, termed the Prader-Willi syndrome imprinting center (PWS-IC), comprises a CpG island that is unmethylated on the paternal allele and methylated on the maternal allele. The second part, termed the Angelman syndrome imprinting centre, is required to silence the PWS_IC in the maternal germline. The loss of the paternal contribution of the imprinted 15q11-q13 locus most frequently occurs owing to a large deletion of the entire imprinted region but can also occur through maternal uniparental disomy or an imprinting defect. While PWS is considered a contiguous gene syndrome based on large-deletion and uniparental disomy patients, the lack of expression of only non-coding RNA transcripts from the may be the primary cause of PWS. Patients with small atypical deletions of the paternal cluster alone appear to have most of the PWS related clinical phenotypes. The loss of the maternal contribution of the 15q11-q13 locus causes a separate and distinct condition called Angelman syndrome. Importantly, while much has been learned about the regulation and expression of genes and transcripts deriving from the 15q11-q13 locus, there remains much to be learned about how these genes and transcripts contribute at the molecular level to the clinical traits and developmental aspects of PWS that have been observed.
Topics: Biomarkers; Chromosomes, Human, Pair 15; Disease Management; Disease Susceptibility; Epigenesis, Genetic; Gene Expression Regulation; Genetic Association Studies; Genetic Loci; Genomic Imprinting; Humans; Phenotype; Prader-Willi Syndrome; RNA, Untranslated
PubMed: 32961075
DOI: 10.1098/rsob.200195 -
Cell Reports Jul 2023The E3 ubiquitin ligase Ube3a is biallelically expressed in neural progenitors and glial cells, suggesting that UBE3A gain-of-function mutations might cause...
The E3 ubiquitin ligase Ube3a is biallelically expressed in neural progenitors and glial cells, suggesting that UBE3A gain-of-function mutations might cause neurodevelopmental disorders irrespective of parent of origin. Here, we engineered a mouse line that harbors an autism-linked UBE3A (T503A in mouse) gain-of-function mutation and evaluated phenotypes in animals that inherited the mutant allele paternally, maternally, or from both parents. We find that paternally and maternally expressed UBE3A results in elevated UBE3A activity in neural progenitors and glial cells. Expression of UBE3A from the maternal allele, but not the paternal one, leads to a persistent elevation of UBE3A activity in neurons. Mutant mice display behavioral phenotypes that differ by parent of origin. Expression of UBE3A, irrespective of its parent of origin, promotes transient embryonic expansion of Zcchc12 lineage interneurons. Phenotypes of Ube3a mice are distinct from Angelman syndrome model mice. Our study has clinical implications for a growing number of disease-linked UBE3A gain-of-function mutations.
Topics: Animals; Mice; Angelman Syndrome; Autistic Disorder; Disease Models, Animal; Gain of Function Mutation; Interneurons; Maternal Inheritance; Phenotype; Ubiquitin-Protein Ligases
PubMed: 37389991
DOI: 10.1016/j.celrep.2023.112706 -
Nature Communications Mar 2023Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability and atypical behaviors. AS results from loss of expression of the E3...
Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability and atypical behaviors. AS results from loss of expression of the E3 ubiquitin-protein ligase UBE3A from the maternal allele in neurons. Individuals with AS display impaired coordination, poor balance, and gait ataxia. PIEZO2 is a mechanosensitive ion channel essential for coordination and balance. Here, we report that PIEZO2 activity is reduced in Ube3a deficient male and female mouse sensory neurons, a human Merkel cell carcinoma cell line and female human iPSC-derived sensory neurons with UBE3A knock-down, and de-identified stem cell-derived neurons from individuals with AS. We find that loss of UBE3A decreases actin filaments and reduces PIEZO2 expression and function. A linoleic acid (LA)-enriched diet increases PIEZO2 activity, mechano-excitability, and improves gait in male AS mice. Finally, LA supplementation increases PIEZO2 function in stem cell-derived neurons from individuals with AS. We propose a mechanism whereby loss of UBE3A expression reduces PIEZO2 function and identified a fatty acid that enhances channel activity and ameliorates AS-associated mechano-sensory deficits.
Topics: Animals; Female; Humans; Male; Mice; Alleles; Angelman Syndrome; Disease Models, Animal; Intellectual Disability; Ion Channels; Linoleic Acid
PubMed: 36859399
DOI: 10.1038/s41467-023-36818-0 -
Journal of Intellectual Disability... Jul 2021Sleep problems are common in many neurodevelopmental disorders, but little is known about how sleep is related to behavioural symptoms in Angelman syndrome (AS) or other...
BACKGROUND
Sleep problems are common in many neurodevelopmental disorders, but little is known about how sleep is related to behavioural symptoms in Angelman syndrome (AS) or other genetic disorders. Hyperactive behaviour, sleep problems and epilepsy seem to be more common in AS than in other genetic conditions associated with severe intellectual disability. We hypothesised that both more sleep problems and earlier onset of epileptic seizures would predict more symptoms of hyperactivity. Hence, the aim of the project was to explore the association between hyperactive behaviour, sleep problems and age of epilepsy onset in individuals with AS.
METHOD
All known parents/guardians (n = 115) of individuals with AS in Norway were invited to participate in this descriptive correlational study. Fifty-six individuals (49%) responded, and 42 people (25 male and 17 female; mean age 18.5 years, range 2-57 years) with genetically verified AS were included. Scores for 'hyperactivity' and 'sleep problems' were derived from questionnaire data. Information on epilepsy was obtained from medical records.
RESULTS
'Hyperactivity' was positively correlated with 'total sleep problems' (r = 0.46, P = 0.002) and negatively correlated with 'age of epilepsy onset' (r = -0.47, P = 0.01). 'Age of epilepsy onset' was not correlated with 'total sleep problems'. An overall multiple regression model with 'hyperactivity' as the dependent variable and 'age of epilepsy onset' and 'total sleep problems' as covariates was significant (R = 0.39, F = 8.16, P = 0.002). Hence, hyperactivity in AS could be predicted from both age of epilepsy onset and current sleep problems.
CONCLUSIONS
Sleep problems may increase hyperactivity symptoms in individuals with AS. The association between hyperactivity and sleep problems in AS indicates that both should be investigated together as part of routine clinical assessment and intervention for either area of difficulty. Younger age of epilepsy onset was associated with more hyperactivity in AS, which may be related to encephalopathic effects of seizures and epilepsy.
Topics: Adolescent; Adult; Angelman Syndrome; Child; Child, Preschool; Epilepsy; Female; Humans; Intellectual Disability; Male; Middle Aged; Sleep Wake Disorders; Surveys and Questionnaires; Young Adult
PubMed: 33951249
DOI: 10.1111/jir.12842 -
Genes Jan 2023Status Epilepticus (SE) is a neurological emergency resulting from the failure of mechanisms of seizure termination or from the initiation of mechanisms that lead to... (Review)
Review
Status Epilepticus (SE) is a neurological emergency resulting from the failure of mechanisms of seizure termination or from the initiation of mechanisms that lead to prolonged seizures. The International League Against Epilepsy (ILAE) identified 13 chromosomal disorders associated with epilepsy (CDAE); data regarding SE occurrence in these patients is lacking. A systematic scoping review was conducted to outline current literature evidence about clinical features, treatments, and outcomes of SE in pediatric and adult patients with CDAE. A total of 373 studies were identified with the initial search; 65 of these were selected and regarded as SE in Angelman Syndrome (AS, = 20), Ring 20 Syndrome (R20, = 24), and other syndromes ( = 21). Non-convulsive status epilepticus (NCSE) is frequently observed in AS and R20. No specific, targeted therapies for SE in CDAE are available to date; anecdotal reports about SE treatment are described in the text, as well as various brief- and long-term outcomes. Further evidence is needed to precisely portray the clinical features, treatment options, and outcomes of SE in these patients.
Topics: Adult; Humans; Child; Status Epilepticus; Epilepsy; Seizures; Chromosome Disorders; Ring Chromosomes
PubMed: 36833226
DOI: 10.3390/genes14020299 -
Journal of Communication Disorders 2022Objective evaluation of receptive communication abilities in nonspeaking individuals using standardized behavioral measures can be complicated by co-occurring...
INTRODUCTION
Objective evaluation of receptive communication abilities in nonspeaking individuals using standardized behavioral measures can be complicated by co-occurring intellectual disabilities and motor difficulties. Eye tracking during listening may offer an informative complementary approach to directly evaluate receptive language skills.
METHOD
This study examined feasibility of eye gaze measures as an index of spoken language comprehension in nonspeaking children and adults with Angelman syndrome (AS; n = 23) using a looking-while-listening procedure. Typically developing children (n = 34) provided a reference data set. Primary caregivers of participants with AS completed standardized informant reports (MacArthur-Bates Communicative Development Inventory: Words and Gestures; Vineland Adaptive Behavior Scales-3; Aberrant Behavior Checklist-2) to characterize communicative skills and general adaptive functioning.
RESULTS
Gaze data in participants with AS, particularly in the individuals reported by caregivers to have larger receptive vocabularies and stronger adaptive communicative functioning, demonstrated the expected pattern of comprehension reflected by the increased probability of looks to the target images after vs. before they were named in a spoken sentence. However, processing speed (gaze reaction time) was significantly slower in participants with AS than in the typically developing group.
CONCLUSIONS
Gaze-based paradigms could be an informative measure of receptive communication processes in participants who are unable to complete traditional standardized behavioral assessments.
Topics: Child; Adult; Humans; Comprehension; Angelman Syndrome; Vocabulary; Language; Gestures
PubMed: 36244082
DOI: 10.1016/j.jcomdis.2022.106272 -
Autism Research : Official Journal of... Jun 2022Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss-of-function mutations in the maternal copy of the UBE3A gene. AS is characterized by intellectual...
Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss-of-function mutations in the maternal copy of the UBE3A gene. AS is characterized by intellectual disability, impaired speech and motor skills, epilepsy, and sleep disruptions. Multiple treatment strategies to re-express functional neuronal UBE3A from the dormant paternal allele were successful in rodent models of AS and have now moved to early phase clinical trials in children. Developing reliable and objective AS biomarkers is essential to guide the design and execution of current and future clinical trials. Our prior work quantified short daytime electroencephalograms (EEGs) to define promising biomarkers for AS. Here, we asked whether overnight sleep is better suited to detect AS EEG biomarkers. We retrospectively analyzed EEGs from 12 overnight sleep studies from individuals with AS with age and sex-matched Down syndrome and neurotypical controls, focusing on low frequency (2-4 Hz) delta rhythms and sleep spindles. Delta EEG rhythms were increased in individuals with AS during all stages of overnight sleep, but overnight sleep did not provide additional benefit over wake in the ability to detect increased delta. Abnormal sleep spindles were not reliably detected in EEGs from individuals with AS during overnight sleep, suggesting that delta rhythms represent a more reliable biomarker. Overall, we conclude that periods of wakefulness are sufficient, and perhaps ideal, to quantify delta EEG rhythms for use as AS biomarkers. LAY SUMMARY: Electroencephalography (EEG) is a safe and reliable way of measuring abnormal brain activity in Angelman syndrome. We found that low-frequency "delta" EEG rhythms are increased in individuals with Angelman syndrome during all stages of overnight sleep. Delta rhythms can be used as a tool to measure improvement in future clinical trials.
Topics: Angelman Syndrome; Autism Spectrum Disorder; Biomarkers; Electroencephalography; Humans; Retrospective Studies; Sleep
PubMed: 35304979
DOI: 10.1002/aur.2709 -
Genetics in Medicine : Official Journal... Feb 2023Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the...
PURPOSE
Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified.
METHODS
Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes.
RESULTS
In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect.
CONCLUSION
HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.
Topics: Humans; Angelman Syndrome; Ubiquitin; Ubiquitin-Protein Ligases; Neurodevelopmental Disorders; Phenotype
PubMed: 36401616
DOI: 10.1016/j.gim.2022.10.006 -
Journal of Neurosurgery. Pediatrics Jun 2022Drug-resistant epilepsy (DRE) affects many children. Vagus nerve stimulation (VNS) may improve seizure control; however, its role in children with genetic etiologies of... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Drug-resistant epilepsy (DRE) affects many children. Vagus nerve stimulation (VNS) may improve seizure control; however, its role in children with genetic etiologies of epilepsy is not well described. The authors systematically reviewed the literature to examine the effectiveness of VNS in this cohort.
METHODS
In January 2021, the authors performed a systematic review of the PubMed/MEDLINE, SCOPUS/Embase, Cochrane, and Web of Science databases to investigate the impact of VNS on seizure outcomes in children with genetic etiologies of epilepsy. Primary outcomes included seizure freedom rate, ≥ 90% seizure reduction rate, and ≥ 50% seizure reduction rate. Secondary outcomes were seizure severity and quality of life (QOL), including cognitive, functional, and behavioral outcomes. A random-effects meta-analysis was performed.
RESULTS
The authors identified 125 articles, of which 47 with 216 nonduplicate patients were analyzed. Common diagnoses were Dravet syndrome (DS) (92/216 patients [42.6%]) and tuberous sclerosis complex (TSC) (63/216 [29.2%]). Seizure freedom was not reported in any patient with DS; the pooled proportion (95% CI) of patients with ≥ 50% seizure reduction was 41% (21%-58%). Secondary cognitive outcomes of VNS were variable in DS patients, but these patients demonstrated benefits in seizure duration and status epilepticus. In TSC patients, the pooled (95% CI) seizure freedom rate was 40% (12%-71%), ≥ 90% seizure reduction rate was 31% (8%-56%), and ≥ 50% reduction rate was 68% (48%-91%). Regarding the secondary outcomes of VNS in TSC patients, several studies reported decreased seizure severity and improved QOL outcomes. There was limited evidence regarding the use of VNS to treat patients with other genetic etiologies of epilepsy, such as mitochondrial disease, Rett syndrome, Doose syndrome, Landau-Kleffner syndrome, Aicardi syndrome, Angelman syndrome, ring chromosome 20 syndrome, and lissencephaly; variable responses were reported in a limited number of cases.
CONCLUSIONS
The authors conducted a systematic review of VNS outcomes in children with genetic etiologies of DRE. Among the most studied conditions, patients with TSC had substantial seizure reduction and improvements in QOL, whereas those with DS had less robust seizure reduction. Increased testing, diagnosis, and long-term follow-up studies are necessary to better characterize VNS response in these children.
Topics: Child; Humans; Quality of Life; Vagus Nerve Stimulation; Drug Resistant Epilepsy; Epilepsy; Seizures; Treatment Outcome; Vagus Nerve; Retrospective Studies
PubMed: 35303699
DOI: 10.3171/2022.1.PEDS222 -
Genes Aug 2022Angelman syndrome (AS) is a neurodevelopmental genetic disorder, but there has been limited analysis of a large cohort of Chinese children with Angelman syndrome. This...
Angelman syndrome (AS) is a neurodevelopmental genetic disorder, but there has been limited analysis of a large cohort of Chinese children with Angelman syndrome. This study aims to assess the phenotype and genotype of Chinese children with Angelman syndrome. We retrospectively analyzed data through a detailed online survey combined with an on-site study. Furthermore, phenotype analysis stratified by deletion and non-deletion groups was carried out. The responses of family members of 695 individuals with AS revealed that 577 patients (83.02%) had maternal deletions, 65 patients (9.35%) carried mutations, 31 (4.46%) patients had UPD15pat (one patient with UPD15pat constituted by a mosaic), 10 patients (1.44%) had imprinting defects and 12 (1.58%) patients only showed abnormal methylation without further detection. We identified 50 different pathogenic variants in this cohort, although 18 of these variants were unreported. Recurrent variant c.2507_2510del (p.K836Rfs*4) was found in 7 patients. In the deletion group, patients were diagnosed at an earlier age, had a more severe clinical phenotype, a higher rate of epilepsy with more multiple seizure types, and more frequently combined medication. Strabismus and sleep disturbances were both common in deletion and non-deletion groups. The top three resources invested in caring for AS children are: daily involvement in patient care, rehabilitation cost, and anti-epileptic treatment. Our study showed the genetic composition of Chinese children with 83.02% of maternal deletions, and the mutation spectrum for variants was expanded. Developmental outcomes are associated with genotype, and this was confirmed by deletion patients having a worse clinical phenotype and complex epilepsy.
Topics: Angelman Syndrome; China; Epilepsy; Genotype; Humans; Phenotype; Retrospective Studies
PubMed: 36011358
DOI: 10.3390/genes13081447