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Angelman syndrome is characterised by neurodevelopmental impairment (with or without epileptic seizures) associated with functional deficit of the UBE3A gene. Different mechanisms of UBE3A inactivation correlate with clinical phenotypes of varying severity. However, three distinctive, highly consistent electroencephalographic rhythmic patterns can...
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Context 1
... electroencephalographic (EEG) abnormalities recognised in the original patients (11) have proved consistent in subsequent studies (08,10,11,14,17,35,55,59,81) and are included in the clinical diagnostic criteria (86). Genetic testing may confirm the diagnosis in around 85% of cases by demonstration obvious abnormalities of chromosome 15911-13 (table 1). All patients with a molecular (or cytogenetic) diagnosis of AS have a functional absence of the maternally inherited UBE3A gene. ...Context 2
... well as contributing to diagnosis both in children (10,86) and in adults (73,80), clinical neurophysiology may therefore still assist our understanding of the complex interactions of the pathophysiology of AS. I-V classes of Angelman syndrome -see Table 1. m-maternally deficient; m+ maternal gene active; ...Citations
... GABA, the main inhibitory neurotransmitter in the central nervous system, has been suggested to play a role in the pathophysiological processes of several neurodevelopmental disorders. [54][55][56][57][58][59][60][61][62] In addition, an age-related reduction in otherwise elevated concentrations of GABA has been associated with motor cortex dysfunction as well as epileptogenesis and autism spectrum disorders in SSADHD. [63][64][65] Plasma GABA concentrations likely reflect its synthesis, accumulation and release from tissues, as well as hepatic and peripheral tissue clearance. ...
Succinic semialdehyde dehydrogenase deficiency is a rare autosomal recessively inherited metabolic disorder of γ-aminobutyric acid catabolism manifested by intellectual disability, expressive aphasia, movement disorders, psychiatric ailments and epilepsy. Subjects with succinic semialdehyde dehydrogenase deficiency are characterized by elevated γ-aminobutyric acid and related metabolites, such as γ-guanidinobutyric acid, and an age-dependent downregulation of cerebral γ-aminobutyric acid receptors. These findings indicate impaired γ-aminobutyric acid and γ-aminobutyric acid sub-type A (GABAA) receptor signalling as major factors underlying the pathophysiology of this neurometabolic disorder. We studied the cortical oscillation patterns and their relationship with γ-aminobutyric acid metabolism in 18 children affected by this condition and 10 healthy controls. Using high-density EEG, we recorded somatosensory cortical responses and resting-state activity. Using electrical source imaging, we estimated the relative power changes (compared with baseline) in both stimulus-evoked and stimulus-induced responses for physiologically relevant frequency bands and resting-state power. Stimulus-evoked oscillations are phase locked to the stimulus, whereas induced oscillations are not. Power changes for both evoked and induced responses as well as resting-state power were correlated with plasma γ-aminobutyric acid and γ-guanidinobutyric acid concentrations and with cortical γ-aminobutyric acid measured by proton magnetic resonance spectroscopy. Plasma γ-aminobutyric acid, γ-guanidinobutyric acid and cortical γ-aminobutyric acid were higher in patients than in controls (P < 0.001 for both). Beta and gamma relative power were suppressed for evoked responses in patients versus controls (P < 0.01). No group differences were observed for induced activity (P > 0.05). The mean gamma frequency of evoked responses was lower in patients versus controls (P = 0.002). Resting-state activity was suppressed in patients for theta (P = 0.011) and gamma (P < 0.001) bands. Evoked power changes were inversely correlated with plasma γ-aminobutyric acid and with γ-guanidinobutyric acid for beta (P < 0.001) and gamma (P < 0.001) bands. Similar relationships were observed between the evoked power changes and cortical γ-aminobutyric acid for all tested areas in the beta band (P < 0.001) and for the posterior cingulate gyrus in the gamma band (P < 0.001). We also observed a negative correlation between resting-state activity and plasma γ-aminobutyric acid and γ-guanidinobutyric acid for theta (P < 0.001; P = 0.003), alpha (P = 0.003; P = 0.02) and gamma (P = 0.02; P = 0.01) bands. Our findings indicate that increased γ-aminobutyric acid concentration is associated with reduced sensory-evoked beta and gamma activity and impaired neuronal synchronization in patients with succinic semialdehyde dehydrogenase deficiency. This further elucidates the pathophysiology of this neurometabolic disorder and serves as a potential biomarker for therapeutic trials.
... 63 GABRB3 ilişkili epileptik ensefalopatiler: Bu gendeki varyantlar; absans epilepsisi, bilişsel gerilik, hatta Angelman sendromu benzeri klinik özellikler gösteren hastalarda tanımlanmıştır. [64][65][66] Nadiren infantil EE'ye neden olur. Hastaların ortak özellikleri, ilk iki ile on ay içinde başlayan infantil spazm, miyoklonik ve davranışsal duraklama şeklinde nöbetler olması, tabloya otistik bulgular ve ağır motor mental retardasyonun eşlik etmesidir. ...
ZET Epileptik ensefalopati tanımı, bilişsel, davranışsal ve diğer beyin işlevlerinde ilerleyici bozul-maya neden olan epileptik sendromlar için kullanılır. Genetik alanındaki gelişmeler, giderek artan sayıda epilepsi ilişkili genin tanımlanmasını sağlamıştır. Epilepsilerin yarısından fazlasının genetik bir etiyo-lojiye sahip olduğu tahmin edilmektedir. Epilepside tanımlanan genlerin yaklaşık %25'i iyon kanalla-rını kodlar. Kanalopatilerin belirgin fenotipik özelliklerini tanımak, uygun tetkikleri yapmak ve daha iyi bakım sağlamak için esastır. Bu bölümde epileptik ensefalopatilere yol açan genetik geçişli kanalopati-ler gözden geçirilmiştir. Anah tar Ke li me ler: Epileptik ensefalopati; fenotip; genetik; genotip; kanalopati ABS TRACT The definition of epileptic encephalopathy is used for epileptic syndromes that cause progressive deterioration in cognitive, behavioral, and other brain functions. Advances in genetics have led to the identification of an increasing number of epilepsy-related genes. It is estimated that more than half of epilepsies have a genetic etiology. About 25% of the genes identified in epilepsy encode ion channels. Recognizing the prominent phenotypical traits of channelopathies is essential to perform appropriate diagnostic investigations and to provide better care. Herein, genetically transmitted chan-nelopathies associated with epileptic encephalopathies are overviewed.
... Расстройство сна может быть связано с нарушением экспрессии гена GABRG3 как вследствие прямой мутации (делеции), так и в связи с нарушением регуляции GABA-A-рецепторов отсутствующим ферментом убиквинтин-лигазой 3а (ube3a). В результате нарушается функция таламо-кортикального пути, что является причиной характерных ЭЭГ-паттернов (ритмичная дельта-активность, зубчатая дельта-активность) и, гипотетически, расстройств архитектоники сна [9]. ...
Sleep disorder is one of the prominent manifestations of Angelman syndrome. The exact causes are unknown and methods of correction are difficult. The literature review is devoted to studies of the pathogenesis of sleep disorders in Angelman syndrome (the effects of gene function in 15q11–q13 deletion, findings in polysomnography, video-EEG sleep monitoring, laboratory data), on the basis of which recommendations for the correction of dyssomnia, including methods of behavioral therapy, are given.
... 35 The effect of these molecules has already been reported, with inconsistent consequences. 15,[36][37][38][39] The existence of gain-of-function mutations may explain the lack of efficacy or the worsening effect of these ASMs and the potential efficacy of sodium channel blockers in some cases. [40][41][42] Although interpreted with substantial caution, the most effective ASMs were different within the three groups in our cohort: valproic acid in the fever-sensitive group, phenobarbital in the DEE group, and lamotrigine in the GGE group. ...
Objective
γ‐Aminobutyric acid (GABA)A‐receptor subunit variants have recently been associated with neurodevelopmental disorders and/or epilepsy. The phenotype linked with each gene is becoming better known. Because of the common molecular structure and physiological role of these phenotypes, it seemed interesting to describe a putative phenotype associated with GABAA‐receptor–related disorders as a whole and seek possible genotype–phenotype correlations.
Methods
We collected clinical, electrophysiological, therapeutic, and molecular data from patients with GABAA‐receptor subunit variants (GABRA1, GABRB2, GABRB3, and GABRG2) through a national French collaboration using the EPIGENE network and compared these data to the one already described in the literature.
Results
We gathered the reported patients in three epileptic phenotypes: 15 patients with fever‐related epilepsy (40%), 11 with early developmental epileptic encephalopathy (30%), 10 with generalized epilepsy spectrum (27%), and 1 patient without seizures (3%). We did not find a specific phenotype for any gene, but we showed that the location of variants on the transmembrane (TM) segment was associated with a more severe phenotype, irrespective of the GABAA‐receptor subunit gene, whereas N‐terminal variants seemed to be related to milder phenotypes.
Significance
GABAA‐receptor subunit variants are associated with highly variable phenotypes despite their molecular and physiological proximity. None of the genes described here was associated with a specific phenotype. On the other hand, it appears that the location of the variant on the protein may be a marker of severity. Variant location may have important weight in the development of targeted therapeutics.
... Frequent clinical characteristics, including microcephaly and seizures, occur in >80% of children with AS, often developing by 3 years of age [17]. A characteristic electroencephalogram (EEG) "signature" can also be found in 80% of children with AS [20,21], which may be an important hint for diagnosis [22]. Children with AS have several associated clinical features (Table 1). ...
Angelman syndrome (AS) is a rare neurodevelopmental disease that is caused by the loss of function of the maternal copy of ubiquitin–protein ligase E3A (UBE3A) on the chromosome 15q11–13 region. AS is characterized by global developmental delay, severe intellectual disability, lack of speech, happy disposition, ataxia, epilepsy, and distinct behavioral profile. There are four molecular mechanisms of etiology: maternal deletion of chromosome 15q11–q13, paternal uniparental disomy of chromosome 15q11–q13, imprinting defects, and maternally inherited UBE3A mutations. Different genetic types may show different phenotypes in performance, seizure, behavior, sleep, and other aspects. AS caused by maternal deletion of 15q11–13 appears to have worse development, cognitive skills, albinism, ataxia, and more autistic features than those of other genotypes. Children with a UBE3A mutation have less severe phenotypes and a nearly normal development quotient. In this review, we proposed to review genotype–phenotype correlations based on different genotypes. Understanding the pathophysiology of the different genotypes and the genotype–phenotype correlations will offer an opportunity for individualized treatment and genetic counseling. Genotype–phenotype correlations based on larger data should be carried out for identifying new treatment modalities.
... Individuals with AS have highly abnormal electroencephalography (EEG) results (13)(14)(15). The most characteristic and robust AS EEG features are excess spontaneous oscillations in the delta frequency range (2-4 Hz) that have been investigated quantitatively in recent years (16)(17)(18)(19). ...
Background
Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by absence of functional UBE3A in neurons. Excess low-frequency oscillations as measured with electroencephalography (EEG) have been identified as a characteristic abnormality, but the relationship to the symptomatology and the pathophysiological significance remains unknown.
Methods
We used correlations and machine learning to investigate the cross-sectional and longitudinal relationship between EEG spectral power and motor, cognitive, and language skills (Bayley Scales of Infant and Toddler Development, Third Edition, Bayley-3), adaptive behavior (Vineland Adaptive Behavioral Scales, Second Edition), AS-specific symptoms (AS Clinical Severity Scale), and the age of epilepsy onset in a large sample of children (age: 1 – 18 years) with AS due to a chromosomal deletion of 15q11-q13 (45 individuals with 72 visits).
Results
We found that, after accounting for age differences, participants with stronger EEG delta-band abnormality had earlier onset of epilepsy and lower performance scores across symptom domains including cognitive, motor and communication. Combing spatial and spectral information beyond the delta frequency band increased the cross-sectional association with clinical severity on average by about 45%. Furthermore, we found evidence for longitudinal correlations of EEG delta-band power within several performance domains, including the mean across Bayley-3 scores.
Conclusions
Our results show an association between EEG abnormalities and symptom severity in AS, underlining the significance of the former in the pathophysiology. Furthermore, our work strengthens the rationale for using EEG as a biomarker in the development of treatments for AS, a concept which may apply more generally to neurodevelopmental disorders.
... The majority of AS patients show a 4-Mb deletion of maternal origin involving three non-imprinted GABA A receptor-subunit genes (GABRB3, GABRA5, and GABRG3, which encode the receptor subunit proteins β3, α5, and γ3, respectively), in addition to UBE3A. The β3 subunit is expressed throughout the brain, especially during development [10] and hemizygosity for this gene may affect the clinical severity of AS through GABAergic dysfunction [11][12][13]. ...
Background
Angelman syndrome (AS) is neurodevelopmental disorder, causal gene of which is maternally expressed UBE3A. A majority of patients results from the large deletion of relevant chromosome which includes GABAA receptor subunit genes (GABARs) as well as UBE3A (AS Del). We previously reported aberrantly desynchronized primary somatosensory response in AS Del by using magnetoencephalography. The purpose of this study is to estimate cortical and subcortical involvement in the deficit of primary somatosensory processing in AS.
Methods
We analyzed short-latency somatosensory-evoked potentials (SSEPs) in 8 patients with AS Del. SSEPs were recorded on a 4-channel system comprising of two cortical electrodes which were placed on the frontal and centro-parietal areas. The peak and onset latency of each component were measured to compare latency and interval times.
Results
The first-cortical peak latency (N20, P20), and N13-N20 peak interval times were significantly prolonged in AS Del compared to healthy controls. In contrast, there was no difference in latencies between subcortical components up to N20 onset or for N11-N20 onset interval times.
Conclusion
Highly desynchronized first-cortical SSEP components and normal latencies of subcortical components indicated cortical dysfunction rather than impairment of afferent pathways in AS Del patients, which might be attributed to GABAergic dysfunction due to loss of UBE3A function and heterozygosity of GABARs
... This receptor plays an important role in seizure disorders, motor control, and cognitive processing [123,124]. Alterations in the GABAA receptor may cause thalamocortical disruptions that lead to the abnormal sleep patterns in AS [124,125]. ...
There are multiple disorders of neurodevelopment that present with co-occurring sleep disturbances. Many of these neurodevelopmental disorders (NDD) include sleep disturbances in their diagnostic criteria. Neurobiological, genetic, and environmental factors overlap to cause different sleep disorders in individuals with NDD. Caregivers often present reporting either insomnia or hypersomnia, and based on the clinical history and findings from diagnostic tests, an appropriate diagnosis can be made. It is crucial that clinicians understand the different presentations of sleep disturbances in individuals with NDD.
... The downstream consequences of UBE3A dysfunction are not understood in detail, but preclinical mouse models of AS show altered dendritic spine morphology (12,13) and impaired synaptic function (14)(15)(16)(17) that may underlie global electrophysiological abnormalities of the electroencephalography (EEG) (15,18,19). These preclinical findings are in line with neuropathological case studies in individuals with AS that point to cellular abnormalities in cortical pyramidal neurons including irregular distribution, decreased dendritic arborization, a reduced number of dendritic spines (20,21), and a strongly abnormal EEG in AS (18,(22)(23)(24). Despite these anomalies, the gross anatomy is not particularly abnormal (25). ...
... AS is characterized by a strongly abnormal EEG (18,(22)(23)(24). Vendrame et al. (23) described EEG abnormalities in a large sample of 115 individuals with AS (here, we analyze a subset of these individuals; see Methods and Materials) and found intermittent rhythmic delta oscillations (83.5%), interictal epileptiform discharges (74.2%), intermittent rhythmic theta oscillations (43.5%), and posterior rhythm slowing (43.5%). ...
... The most prominent difference between AS genotypes, however, was not anticipated by our hypotheses: oscillatory activity in the theta frequency range, which is present only for the deletion AS genotype. Rhythmic theta in AS has been qualitatively described in previous publications (23,24,55,56), but to the best of our knowledge, our work is the first to quantify excess theta oscillations and to link them to the deletion AS genotype. Given that GABA A receptors are critically involved in shaping neuronal dynamics reflected in EEG oscillations (37)(38)(39), deletion of the GABRB3-GABRA5-GABRG3 gene cluster is the most likely cause of the AS genotype differences observed in our study. ...
Background:
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by either disruptions of the gene UBE3A or deletion of chromosome 15 at 15q11-q13, which encompasses UBE3A and several other genes, including GABRB3, GABRA5, GABRG3, encoding gamma-aminobutyric acid type A receptor subunits (β3, α5, γ3). Individuals with deletions are generally more impaired than those with other genotypes, but the underlying pathophysiology remains largely unknown. Here, we used electroencephalography (EEG) to test the hypothesis that genes other than UBE3A located on 15q11-q13 cause differences in pathophysiology between AS genotypes.
Methods:
We compared spectral power of clinical EEG recordings from children (1-18 years of age) with a deletion genotype (n = 37) or a nondeletion genotype (n = 21) and typically developing children without Angelman syndrome (n = 48).
Results:
We found elevated theta power (peak frequency: 5.3 Hz) and diminished beta power (peak frequency: 23 Hz) in the deletion genotype compared with the nondeletion genotype as well as excess broadband EEG power (1-32 Hz) peaking in the delta frequency range (peak frequency: 2.8 Hz), shared by both genotypes but stronger for the deletion genotype at younger ages.
Conclusions:
Our results provide strong evidence for the contribution of non-UBE3A neuronal pathophysiology in deletion AS and suggest that hemizygosity of the GABRB3-GABRA5-GABRG3 gene cluster causes abnormal theta and beta EEG oscillations that may underlie the more severe clinical phenotype. Our work improves the understanding of AS pathophysiology and has direct implications for the development of AS treatments and biomarkers.
... Distinctive sleep problems or disorders are scarcely reported. On the one hand, abnormal encephalogram (EEG) patterns [6,9] were found to be sufficiently distinguishing to help identify AS at an early age. These patterns basically involve either characteristic rhythmic patterns (unrelated to epilepsy) or less specific epilepsyrelated discharge activity. ...
... These patterns basically involve either characteristic rhythmic patterns (unrelated to epilepsy) or less specific epilepsyrelated discharge activity. Based on these features a model of cortical and thalamo-cortical dysfunction has been proposed [6]. Unfortunately, the observed EEG rhythmic patterns, in part due to their transient nature, might be common in chromosomal disorders in general. ...
... In sum, our finding of arousal difficulties pooled with the other significant sleep disorder item-groups, may support the thalamocortical dysfunction model [6] with its two characteristic patterns; that is, one related and one not related to epilepsy. A dysfunction thought to be resulting from dysregulation of synaptic GABAergic neurotransmission. ...
Sleep problems are reported to be extremely prevalent in individuals with developmental disabilities. The consensus guidelines for Angelman syndrome (AS) consider abnormal sleep-wake cycles and diminished need for sleep as associated features. We report an integrative research review and a meta-analysis of studies with sleep as the primary aim of investigation in an AS sample. 14 studies met eligibility criteria with half of them being surveys. Thirteen of the 17 conceptually formed sleep disorder item-groups showed to be significant for individuals with AS. There is evidence that arousal during sleep, somnolence and possibly short sleep duration are the primary sleep problems in individuals with AS. According to the results of this review and meta-analyses, there is clear evidence for sleep problems in individuals with AS. Individual effect sizes remain overall small, but nevertheless findings suggest disorders of arousal and sleepiness to be distinctive. In light of these findings, other sleep complaints in individuals with AS should be carefully examined. Consistent standards for research on sleep in individuals with AS are critical for new lines of investigation.
