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Angelman syndrome (AS) is a genetic disorder characterised by severe mental retardation, subtle dysmorphic facial features, a characteristic behavioural phenotype, epileptic seizures and EEG abnormalities. AS can be caused by various genetic mechanisms involving the chromosome 15q11-13 region. Neurophysiological studies report a variety of EEG abno...
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... are only few publi- cations on this subject. EEG abnormalities are much more prominent in AS patients with a deletion (97 -100%) and not so pronounced in those with other genetic disturbances (UBE3A mutation, uniparental disomy, methylation dis- turbances [9,10] [ Table 1]). In the studies of Matsumoto et al. [6] and Minassian et al. [10] all patients with large chromosome 15q11 -13 deletions had distinct EEG abnorm- alities of slow and a disorganised background rhythm in combination with bursts of slow (2 -3 Hz) triphasic waves or spike waves. ...
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... Current findings suggest that WHS EEG features look different from those reported in Angelman syndrome [1,57]. The fast spike-polyspike-wave complexes triggered by eye closure over the posterior brain regions in WHS are not observed in individuals with Angelman syndrome, in whom the abnormalities detected posteriorly are slower and less well defined [1,58]; the anteriorly prominent large-amplitude slow activity seen in Angelman syndrome [1,58] is not observed in WHS; finally, the distinct fast-bursting cortical myoclonus of Angelman syndrome has never been detected in WHS [1,59]. ...
Wolf–Hirschhorn syndrome (WHS) is a rare disorder with an estimated prevalence being around 1 in 50,000 births. The syndrome is caused by the deletion of a critical region (Wolf–Hirschhorn Syndrome Critical region- WHSCR) on chromosome 4p16.3. WHS is clinically characterized by pre-and postnatal growth restriction, hypotonia, intellectual disability, craniofacial dysmorphismand congenital fusion anomalies. The clinical aspects are variable due to the deletion size. Consistently, epilepsy is one of the major concerns for parents and professionals caring for children with WHS. Seizures tend to occur in over 90% of patients, with onset within the first 3 years of life, and a peak incidence at around 6–12 months of age. Approximately 20% of patients had the first seizure onset within the first 6 months of age, almost 50% at 6 to 12 months of age and about 25% later than 12 months of age. The main types of epileptic seizures occurring in patients with WHS were generalized tonic–clonic seizures (around 70%). These were followed by tonic spasms (20%); focal seizures with impaired awareness (12%) and clonicseizures in 7% of patients. Seizures are often triggered by fever, followed by infections of various systems. Particularly, half of WHS patients experience status epilepticus in the first years of life, which can be fatal. Due to limited number of reports on the topic of EEG abnormalities in epilepsy among WHS patients, it is difficult to determine whether there are any characteristic deviations for WHS. Although more than 300 persons with WHS have been reported in the literature, there is sparse knowledge about epilepsy and methods of its anti-seizure medication (ASM) management with an assessment of their effectiveness. The purpose of this systematic review is to briefly summarize achievements and advances in the field of epilepsy in Wolf-Hirschhorn syndrome.
... Differential diagnosis is mainly based on clinical findings. Although AS has a characteristic EEG pattern, MRI and EEG studies do not suggest specific diagnostic leads for the mentioned syndromes [8]. AS mostly presents with unmotivated laughing episodes, seizures, and microcephaly. ...
Pitt-Hopkins syndrome (PTHS) is characterized by developmental delay, intellectual disability and behavioral changes, distinctive facial gestalt, and breathing abnormalities. PTHS is caused by deletions or pathological variants in the TCF4 gene located at 18q21.2. In this report, we aimed to describe the clinical and genetic findings of patients diagnosed with PTHS and compare our patients with the literature. Patients who were followed up with severe intellectual disability and a variable association of features previously described as characteristic of the PTHS phenotype in the pediatric neurology clinic of Antalya Training and Research Hospital were screened for TCF4 mutations using next-generation sequencing (NGS)-based tests, between 2017 and 2020. A genetic mutation associated with PTHS was detected in five patients. This paper emphasis on mutational and clinical spectrum of PTHS and its significant part in the differential diagnosis of severe mental retardation
... 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.
... In conclusion, this work resolves the apparent paradox of wakeful, purposefully behaving, children with AS exhibiting an EEG phenotype most typically associated with states of low/no consciousness (Laan and Vein 2005;Vendrame et al. 2012;Frohlich et al. 2019a). By finding complex brain dynamics that are sensitive to relative level of consciousness even under conditions of extreme cortical hypersychronization, these results suggest that high-voltage, slow EEG activity is not a reliable indicator of unconsciousness. ...
Abundant evidence from slow wave sleep, anesthesia, coma, and epileptic seizures links high-voltage, slow electroencephalogram (EEG) activity to loss of consciousness. This well-established correlation is challenged by the observation that children with Angelman syndrome (AS), while fully awake and displaying volitional behavior, display a hypersynchronous delta (1–4 Hz) frequency EEG phenotype typical of unconsciousness. Because the trough of the delta oscillation is associated with down-states in which cortical neurons are silenced, the presence of volitional behavior and wakefulness in AS amidst diffuse delta rhythms presents a paradox. Moreover, high-voltage, slow EEG activity is generally assumed to lack complexity, yet many theories view functional brain complexity as necessary for consciousness. Here, we use abnormal cortical dynamics in AS to assess whether EEG complexity may scale with the relative level of consciousness despite a background of hypersynchronous delta activity. As characterized by multiscale metrics, EEGs from 35 children with AS feature significantly greater complexity during wakefulness compared with sleep, even when comparing the most pathological segments of wakeful EEG to the segments of sleep EEG least likely to contain conscious mentation and when factoring out delta power differences across states. These findings (i) warn against reverse inferring an absence of consciousness solely on the basis of high-amplitude EEG delta oscillations, (ii) corroborate rare observations of preserved consciousness under hypersynchronization in other conditions, (iii) identify biomarkers of consciousness that have been validated under conditions of abnormal cortical dynamics, and (iv) lend credence to theories linking consciousness with complexity.
... In conclusion, this work resolves the apparent paradox of wakeful, purposefully behaving, children with AS exhibiting an EEG phenotype most typically associated with states of low/no consciousness (Laan and Vein 2005;Vendrame et al. 2012;Frohlich et al. 2019a). By finding complex brain dynamics that are sensitive to relative level of consciousness even under conditions of extreme cortical hypersychronization, these results suggest that high-voltage, slow EEG activity is not a reliable indicator of unconsciousness. ...
Numerous theories link consciousness to informationally rich, complex neural dynamics. This idea is challenged by the observation that children with Angelman syndrome (AS), while fully conscious, display a hypersynchronous electroencephalogram (EEG) phenotype typical of information-poor dynamics associated with unconsciousness. If informational complexity theories are correct, then sufficiently complex dynamics must still exist during wakefulness and exceed that observed in sleep despite pathological delta (1 - 4 Hz) rhythms in children with AS. As characterized by multiscale metrics, EEGs from 35 children with AS feature significantly greater complexity during wakefulness compared with sleep, even when comparing the most pathological segments of wakeful EEG to the segments of sleep EEG least likely to contain conscious experiences, and when factoring out delta power differences across states. These findings support theories linking consciousness with complexity and warn against reverse inferring an absence of consciousness solely on the basis of clinical readings of EEG.
... [9] The distinguishing features in AS are the absence of changes in EEG from awake to sleeping state and a less chaotic background. [10] A new-onset tremulousness and clinicoelectrographic discordance with hypsarrhythmia pattern in the absence of clinically evident epileptic spasms, are additional clues to AS in very young children. Furthermore, it is imperative to rule out AS in undiagnosed children with refractory epilepsy, maladaptive behavioral phenotype, and severe intellectual disability. ...
... 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%). ...
... We found excess delta oscillations to be the most prominent AS EEG phenotype. This result agrees with clinical observations of qualitatively abnormal EEG activity in AS (22,49,50) and a recent publication by Sidorov et al. (18) that demonstrated a robust increase in relative power in the same frequency range. Our results extend previous work in several directions. ...
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.
... AS-related electroencephalographic abnormalities fall into several classic patterns, varying according to age and genotype [16,17]. The most frequent pattern is rhythmic delta activity of 2-3 Hz with high amplitude (200-500 μV) superimposed on multifocal spike and sharp waves in the prolonged period [20]. Frequently, the EEG discharge has a notched appearance [20,23] and monorhythmic 4-5-Hz activity may be recorded over the posterior scalp [4]. ...
... The most frequent pattern is rhythmic delta activity of 2-3 Hz with high amplitude (200-500 μV) superimposed on multifocal spike and sharp waves in the prolonged period [20]. Frequently, the EEG discharge has a notched appearance [20,23] and monorhythmic 4-5-Hz activity may be recorded over the posterior scalp [4]. These discharges are symmetric and synchronous [4]. ...
Background:
We describe three children with Angelman syndrome and medically refractory epilepsy.
Methods:
Case series of three pediatric patients with Angelman syndrome and medically refractory epilepsy. All three patients failed medical treatment and were recommended for vagal nerve stimulator (VNS) implantation.
Results:
Following VNS implantation, all three patients experienced reduction in seizure frequency greater than that afforded by medication alone.
Conclusion:
We present vagal nerve stimulator implantation as a viable treatment option for medically refractory epilepsy associated with Angelman syndrome.
... Because of lack of specifi city of the epilepsy syndromes, chromosomal disorders are recognized based on more distinctive features such as the "Greek helmet" appearance in WHS; the presence of lissencephaly in MDS; the craniofacial features, lack of speech, and distal myoclonus in AMS; and the retinal abnormalities in r14 (188). WHS and AMS also have characteristic EEG fi ndings (191,192). The absence of dysmorphism and overt cognitive defi cits makes r20 diffi cult to recognize (188). ...
https://www.medschool.lsuhsc.edu/epilepsy_center/docs/Epilepsy%20Syndromes.pdf
... Population prevalence of Angelman syndrome has been calculated at 1 : 20,000-1 : 120,000 in children constituting 1.4% to 3% of all cases of severe mental retardation and about 6% of all cases with mental retardation with active epilepsy; both sexes are affected equally [1]. It is characterized clinically by a severe developmental delay, absence of speech, motor impairment, epilepsy, and a peculiar behavioral phenotype [2] as well as associated sleep disturbances and EEG abnormalities that can be used as an ancillary tool for Angelman syndrome patients [3]. The clinical diagnosis of the disease can be confirmed either by cytogenetic or DNA testing in about 80-85% of cases. ...
The main aim of the study was to compare the melatonin rhythms in subjects with Angelman syndrome ( n=9 ) and in children with ( n=80 ) and without ( n=40 ) epilepsy (nonepileptic patients diagnosed with peripheral nerve palsies, myopathy, and back pain) using our mathematical model of melatonin circadian secretion. The characteristics describing the diurnal hormone secretion such as minimum melatonin concentration, release amplitude, phase shift of melatonin release, and sleep duration as well as the dim light melatonin onset (DLMO) of melatonin secretion and the γ shape parameter allow analyzing the fit and deducing about how much the measured melatonin profile differs from a physiological bell-shaped secretion. The estimated sleep duration and phase shift of melatonin release as well as the DMLO offsets at 25% and 50% relative thresholds are the key characteristic of Angelman syndrome children. As revealed from the γ shape parameter, the melatonin secretion profiles are disturbed in majority of the AG subjects revealing rather a triangular course instead of the bell-like one.
