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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 -
Zhurnal Nevrologii I Psikhiatrii Imeni... 2022Angelman's syndrome (AS) is accompanied by specific changes in the EEG and genetically determined epilepsy. To analyze the neurological status, changes on EEG, MRI, the...
OBJECTIVE
Angelman's syndrome (AS) is accompanied by specific changes in the EEG and genetically determined epilepsy. To analyze the neurological status, changes on EEG, MRI, the course of epilepsy in patients with Angelman syndrome (observed at the Svt. uca`s Institute of Child Neurology and Epilepsy).
MATERIAL AND METHODS
47 patients with a genetically verified diagnosis of AS (aged 2 to 20 years, mean age 8.5 years; 26 boys and 21 girls) were included. The diagnosis was established by DNA methylation in 32 patients and sequencing in 15 patients (12 cases of deletion and 3 cases of nucleotide substitution were identified).
RESULTS
Of the 47 patients, 45 have epilepsy. The seizures start up to 5 years of age, inclusive. For treatment, patients received various antiepileptic drugs. Long-term follow-up of epilepsy was followed in 40 of 47 patients, and 36 of 40 achieved drug remission. After several years without seizures, 24 out of 30 had a relapse, which was quickly stopped in 23 out of 30 patients. The severity of the disease is influenced by the nature of the mutation and the length of the deletion, as well as persistent epileptic seizures. The most effective AEDs in patients in our study are: in monotherapy, valproic acid, levetiraceiam, ethosuximide; in duotherapy, valproic acid in combination with levetiracetam or ethosuximide, less often levetiracetam with ethosuximide.
CONCLUSIONS
Early genetic diagnosis of AS facilitates the selection of AET.
Topics: Angelman Syndrome; Anticonvulsants; Child; Electroencephalography; Epilepsy; Ethosuximide; Female; Humans; Levetiracetam; Male; Seizures; Valproic Acid
PubMed: 35904299
DOI: 10.17116/jnevro2022122071100 -
Journal of Neurodevelopmental Disorders Feb 2023Angelman syndrome (AS) is a neurodevelopmental disorder with serious seizures. We aim to explore the brain morphometry of patients with AS and figure out whether the...
BACKGROUND
Angelman syndrome (AS) is a neurodevelopmental disorder with serious seizures. We aim to explore the brain morphometry of patients with AS and figure out whether the seizure is associated with brain development.
METHODS
Seventy-three patients and 26 healthy controls (HC) underwent high-resolution structural brain MRI. Group differences between the HC group and the AS group and also between AS patients with seizure (AS-Se) and age-matched AS patients with non-seizure (AS-NSe) were compared. The voxel-based and surface-based morphometry analyses were used in our study. Gray matter volume, cortical thickness (CTH), and local gyrification index (LGI) were assessed to analyze the cortical and subcortical structure alteration in the AS brain.
RESULTS
Firstly, compared with the HC group, children with AS were found to have a significant decrease in gray matter volume in the subcortical nucleus, cortical, and cerebellum. However, the gray matter volume of AS patients in the inferior precuneus was significantly increased. Secondly, patients with AS had significantly increased LGI in the whole brain as compared with HC. Thirdly, the comparison of AS-Se and the AS-NSe groups revealed a significant decrease in caudate volume in the AS-Se group. Lastly, we further selected the caudate and the precuneus as ROIs for volumetric analysis, the AS group showed significantly increased LGI in the precuneus and reduced CTH in the right precuneus. Between the AS-Se and the AS-NSe groups, the AS-Se group exhibited significantly lower density in the caudate, while only the CTH in the left precuneus showed a significant difference.
CONCLUSIONS
These results revealed cortical and subcortical morphological alterations in patients with AS, including globally the decreased brain volume in the subcortical nucleus, the increased gray matter volume of precuneus, and the whole-brain increase of LGI and reduction of CTH. The abnormal brain pattern was more serious in patients with seizures, suggesting that the occurrence of seizures may be related to abnormal brain changes.
Topics: Child; Humans; Angelman Syndrome; Brain; Gray Matter; Magnetic Resonance Imaging; Parietal Lobe; Seizures
PubMed: 36788499
DOI: 10.1186/s11689-022-09469-3 -
Orphanet Journal of Rare Diseases Apr 2024Angelman syndrome (AS) is a neurodevelopmental disorder caused by abnormal expression of the maternal ubiquitin protein ligase E3A gene (UBE3A). As one of the most... (Review)
Review
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.
Topics: Animals; Humans; Angelman Syndrome; Sleep; Sleep Wake Disorders; Ubiquitin-Protein Ligases
PubMed: 38580983
DOI: 10.1186/s13023-024-03154-5 -
Neuroscience Oct 2020The UBE3A gene is part of the chromosome 15q11-q13 region that is frequently deleted or duplicated, leading to several neurodevelopmental disorders (NDD). Angelman... (Review)
Review
The UBE3A gene is part of the chromosome 15q11-q13 region that is frequently deleted or duplicated, leading to several neurodevelopmental disorders (NDD). Angelman syndrome (AS) is caused by the absence of functional maternally derived UBE3A protein, while the paternal UBE3A gene is present but silenced specifically in neurons. Patients with AS present with severe neurodevelopmental delay, with pronounced motor deficits, absence of speech, intellectual disability, epilepsy, and sleep problems. The pathophysiology of AS is still unclear and a treatment is lacking. Animal models of AS recapitulate the genotypic and phenotypic features observed in AS patients, and have been invaluable for understanding the disease process as well as identifying apropriate drug targets. Using these AS mouse models we have learned that loss of UBE3A probably affects many areas of the brain, leading to increased neuronal excitability and a loss of synaptic spines, along with changes in a number of distinct behaviours. Inducible AS mouse models have helped to identify the critical treatment windows for the behavioral and physiological phenotypes. Additionally, AS mouse models indicate an important role for the predominantly nuclear UBE3A isoform in generating the characteristic AS pathology. Last, but not least, the AS mice have been crucial in guiding Ube3a gene reactivation treatments, which present a very promising therapy to treat AS.
Topics: Angelman Syndrome; Animals; Disease Models, Animal; Humans; Male; Mice; Neurons; Phenotype; Ubiquitin-Protein Ligases
PubMed: 32088294
DOI: 10.1016/j.neuroscience.2020.02.017 -
Current Opinion in Psychiatry Mar 2021This review describes current understandings in the search for therapies to support children with Angelman syndrome. There is a rapid progression in particular in... (Review)
Review
PURPOSE OF REVIEW
This review describes current understandings in the search for therapies to support children with Angelman syndrome. There is a rapid progression in particular in genetic therapies in this disorder supported by the Angelman community.
RECENT FINDINGS
Recent papers shed light on the timing of therapies and novel genetic therapies coming to trial as well as potential therapies still in preclinical phases. Further understanding of UBE3A and its role in neuronal development and plasticity as well as other mechanisms contributing to the Angelman phenotype is offering an opportunity for novel therapeutics.
SUMMARY
Greater understanding of the pathophysiology of the different phenotypes will offer an opportunity for novel therapeutics and may well change the course of this disorder over time where previously there has been minimal ability to intervene.
Topics: Angelman Syndrome; Genetic Therapy; Humans; Phenotype; Ubiquitin-Protein Ligases
PubMed: 33395098
DOI: 10.1097/YCO.0000000000000674 -
Current Gene Therapy 2020Angelman Syndrome (AS) is a congenital non inherited neurodevelopmental disorder. The contemporary AS management is symptomatic and it has been accepted that gene... (Review)
Review
BACKGROUND
Angelman Syndrome (AS) is a congenital non inherited neurodevelopmental disorder. The contemporary AS management is symptomatic and it has been accepted that gene therapy may play a key role in the treatment of AS.
OBJECTIVE
The purpose of this study is to summarize existing and suggested gene therapy approaches to Angelman syndrome.
METHODS
This is a literature review. Pubmed and Scopus databases were researched with keywords (gene therapy, Angelman's syndrome, neurological disorders, neonates). Peer-reviewed studies that were closely related to gene therapies in Angelman syndrome and available in English, Greek, Ukrainian or Indonesian were included. Studies that were published before 2000 were excluded and did not align with the aforementioned criteria.
RESULTS
UBE3A serves multiple roles in signaling and degradation procedures. Although the restoration of UBE3A expression rather than targeting known activities of the molecule would be the optimal therapeutic goal, it is not possible so far. Reinstatement of paternal UBE3A appears as an adequate alternative. This can be achieved by administering topoisomerase-I inhibitors or reducing UBE3A antisense transcript (UBE3A-ATS), a molecule which silences paternal UBE3A.
CONCLUSION
Understanding UBE3A imprinting unravels the path to an etiologic treatment of AS. Gene therapy models tested on mice appeared less effective than anticipated pointing out that activation of paternal UBE3A cannot counteract the existing CNS defects. On the other hand, targeting abnormal downstream cell signaling pathways has provided promising rescue effects. Perhaps, combined reinstatement of paternal UBE3A expression with abnormal signaling pathways-oriented treatment is expected to provide better therapeutic effects. However, AS gene therapy remains debatable in pharmacoeconomics and ethics context.
Topics: Angelman Syndrome; Animals; Anti-Anxiety Agents; Antiparkinson Agents; Buspirone; Diet, Ketogenic; Dietary Supplements; Disease Models, Animal; Gene Silencing; Genetic Therapy; Humans; Levodopa; Mice; Minocycline; Neurons; Signal Transduction; Topoisomerase I Inhibitors; Ubiquitin-Protein Ligases
PubMed: 31914913
DOI: 10.2174/1566523220666200107151025 -
Expert Opinion on Investigational Drugs Jul 2021: Angelman syndrome is a rare genetic neurodevelopmental disorder, caused by deficiency or abnormal function of the maternal ubiquitin protein-ligase E3A, known as... (Review)
Review
: Angelman syndrome is a rare genetic neurodevelopmental disorder, caused by deficiency or abnormal function of the maternal ubiquitin protein-ligase E3A, known as UBE3A, in the central nervous system. There is no disease-modifying treatment available, but the therapeutic pipeline of Angelman syndrome includes at least 15 different approaches at preclinical or clinical development. In the coming years, several clinical trials will be enrolling patients, which prompted this comprehensive review.: We summarize and critically review the different therapeutic approaches. Some approaches attempt to restore the missing or nonfunctional UBE3A protein in the neurons via gene replacement or enzyme replacement therapies. Other therapies aim to induce expression of the normal paternal copy of the gene by targeting a long non-coding RNA, the , which interferes with its own expression. Another therapeutic category includes compounds that target molecular pathways and effector proteins known to be involved in Angelman syndrome pathophysiology.: We believe that by 2022-2023, more than five disease-modifying treatments will be simultaneously at clinical testing. However, the are several challenges with regards to safety and efficacy, which need to be addressed. Additionally, there is still a significant unmet need for clinical trial readiness.
Topics: Angelman Syndrome; Animals; Enzyme Replacement Therapy; Genetic Therapy; Humans; Ubiquitin-Protein Ligases
PubMed: 34112038
DOI: 10.1080/13543784.2021.1939674 -
International Journal of Molecular... Sep 2021Angelman-like syndromes are a group of neurodevelopmental disorders that entail clinical presentation similar to Angelman Syndrome (AS). In our previous study, we showed...
Angelman-like syndromes are a group of neurodevelopmental disorders that entail clinical presentation similar to Angelman Syndrome (AS). In our previous study, we showed that calcium signaling is disrupted in AS, and we identified calcium-target and calcium-regulating gene signatures that are able to differentiate between AS and their controls in different models. In the herein study, we evaluated these sets of calcium-target and calcium-regulating genes as signatures of AS-like and non-AS-like syndromes. We collected a number of RNA-seq datasets of various AS-like and non-AS-like syndromes and performed Principle Component Analysis (PCA) separately on the two sets of signature genes to visualize the distribution of samples on the PC1-PC2 plane. In addition to the evaluation of calcium signature genes, we performed differential gene expression analyses to identify calcium-related genes dysregulated in each of the studied syndromes. These analyses showed that the calcium-target and calcium-regulating signatures differentiate well between AS-like syndromes and their controls. However, in spite of the fact that many of the non-AS-like syndromes have multiple differentially expressed calcium-related genes, the calcium signatures were not efficient classifiers for non-AS-like neurodevelopmental disorders. These results show that features based on clinical presentation are reflected in signatures derived from bioinformatics analyses and suggest the use of bioinformatics as a tool for classification.
Topics: Angelman Syndrome; Calcium; Calcium Signaling; Chromosome Deletion; Computational Biology; Gene Expression Regulation; Humans; Principal Component Analysis; RNA-Seq
PubMed: 34576033
DOI: 10.3390/ijms22189870 -
Developmental Medicine and Child... Nov 2019A scoping review was conducted to examine and evaluate empirical data on the communication profile of Angelman syndrome beyond the described dissociation between... (Review)
Review
AIM
A scoping review was conducted to examine and evaluate empirical data on the communication profile of Angelman syndrome beyond the described dissociation between receptive language and speech.
METHOD
Three databases (PsycINFO, Embase, and Web of Science) were searched to retrieve articles investigating communication in Angelman syndrome. Seventeen articles investigating the broader communication profile were found; their methodology was evaluated against quality criteria.
RESULTS
Despite the absence of speech, individuals with Angelman syndrome have a wide repertoire of non-verbal communicative behaviours, mainly characterized by gestures, although advanced forms such as symbolic communication are used by some individuals. The use of communicative forms differs between the genetic aetiologies of Angelman syndrome; individuals with non-deletion aetiologies typically have greater communicative abilities.
INTERPRETATION
The broader communication profile of Angelman syndrome is characterized by diverse and multimodal abilities, including some use of symbolic forms of communication that appears atypical given the absence of speech. This is suggestive of a probable dissociation between speech and other expressive forms of communication, indicating an isolated speech production impairment. This highlights a need in this population for alternative communication and specific input from services tailored to support the nuances of the communication profile of Angelman syndrome.
WHAT THIS PAPER ADDS
Although absent speech is near universal, a diverse profile of other communicative abilities has been reported. Parental reporting has been predominantly used to assess the communication profile of Angelman syndrome. Literature that investigates the specificities and possible dissociations in such a communication profile is limited.
Topics: Angelman Syndrome; Communication; Humans; Nonverbal Communication; Speech
PubMed: 31074506
DOI: 10.1111/dmcn.14257