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Epileptic Disorders : International... Dec 2023This study aimed to assess the long-term effectiveness and seizure recurrence risk in children with drug-resistant epilepsy who achieved seizure freedom on a ketogenic...
OBJECTIVE
This study aimed to assess the long-term effectiveness and seizure recurrence risk in children with drug-resistant epilepsy who achieved seizure freedom on a ketogenic diet (KD). Predictors associated with seizure recurrence were also evaluated.
METHODS
Patients with drug-resistant epilepsy who received KD therapy for at least 3 months between May 2011 and April 2020 were included. The clinical efficacy of the KD was evaluated. Patients who achieved seizure freedom for at least 3 months on the KD were focused. Multivariate Cox regression models were used to explore the risk factors of seizure relapse in patients who achieved seizure freedom.
RESULTS
This study included 288 patients (163 males, 125 females). The seizure-free rates of the KD at 3, 6, 12, and 24 months were 9.7%, 16.7%, 14.2%, and 9.0%, respectively. Additionally, the seizure reduction rates between 50% and 99% were 46.5%, 39.9%, 30.2%, and 20.5%, respectively. Patients with Angelman syndrome (AS) showed the highest efficacy rate, followed by those with Dravet syndrome (DS). 51 patients achieved at least 3 months of seizure freedom on the KD. Seizures recurred in 24 (47.1%) patients. None of the patients with AS relapsed, while those with DS had the highest recurrence rate. The etiology of epilepsy, KD maintenance treatment period, and electroencephalography (EEG) abnormalities during follow-up differed significantly between patients with and without recurrence. However, multivariate Cox regression analysis indicated that a KD maintenance treatment period of less than 12 months and the presence of EEG abnormalities during follow-up were significantly correlated with a higher risk of relapse. Epilepsy control was restored in 3 of the 24 (12.5%) patients who experienced relapse.
SIGNIFICANCE
KD appears to be effective in children with various types of drug-resistant epilepsy. A short KD maintenance treatment period and EEG abnormalities during follow-up were associated with an increased risk of seizure recurrence.
Topics: Male; Female; Child; Humans; Drug Resistant Epilepsy; Diet, Ketogenic; Tertiary Care Centers; Seizures; Epilepsy; Treatment Outcome; Risk Factors; Epilepsies, Myoclonic; China; Recurrence; Retrospective Studies
PubMed: 37712490
DOI: 10.1002/epd2.20160 -
Science (New York, N.Y.) Sep 2023Inactivation of the ubiquitin ligase Ube3a causes the developmental disorder Angelman syndrome, whereas increased Ube3a dosage is associated with autism spectrum...
Inactivation of the ubiquitin ligase Ube3a causes the developmental disorder Angelman syndrome, whereas increased Ube3a dosage is associated with autism spectrum disorders. Despite the enriched localization of Ube3a in the axon terminals including presynapses, little is known about the presynaptic function of Ube3a and mechanisms underlying its presynaptic localization. We show that developmental synapse elimination requires presynaptic Ube3a activity in neurons. We further identified the domain of Ube3a that is required for its interaction with the kinesin motor. Angelman syndrome-associated missense mutations in the interaction domain attenuate presynaptic targeting of Ube3a and prevent synapse elimination. Conversely, increased Ube3a activity in presynapses leads to precocious synapse elimination and impairs synaptic transmission. Our findings reveal the physiological role of Ube3a and suggest potential pathogenic mechanisms associated with Ube3a dysregulation.
Topics: Animals; Angelman Syndrome; Autism Spectrum Disorder; Down-Regulation; Drosophila Proteins; Synaptic Transmission; Ubiquitin-Protein Ligases; Drosophila melanogaster; Synapses
PubMed: 37708280
DOI: 10.1126/science.ade8978 -
BioRxiv : the Preprint Server For... Aug 2023Angelman Syndrome (AS) and Prader-Willi Syndrome (PWS), two distinct neurodevelopmental disorders, result from loss of expression from imprinted genes in the chromosome...
Angelman Syndrome (AS) and Prader-Willi Syndrome (PWS), two distinct neurodevelopmental disorders, result from loss of expression from imprinted genes in the chromosome 15q11-13 locus most commonly caused by a megabase-scale deletion on either the maternal or paternal allele, respectively. Each occurs at an approximate incidence of 1/15,000 to 1/30,000 live births and has a range of debilitating phenotypes. Patient-derived induced pluripotent stem cells (iPSCs) have been valuable tools to understand human-relevant gene regulation at this locus and have contributed to the development of therapeutic approaches for AS. Nonetheless, gaps remain in our understanding of how these deletions contribute to dysregulation and phenotypes of AS and PWS. Variability across cell lines due to donor differences, reprogramming methods, and genetic background make it challenging to fill these gaps in knowledge without substantially increasing the number of cell lines used in the analyses. Isogenic cell lines that differ only by the genetic mutation causing the disease can ease this burden without requiring such a large number of cell lines. Here, we describe the development of isogenic human embryonic stem cell (hESC) lines modeling the most common genetic subtypes of AS and PWS. These lines allow for a facile interrogation of allele-specific gene regulation at the chromosome 15q11-q13 locus. Additionally, these lines are an important resource to identify and test targeted therapeutic approaches for patients with AS and PWS.
PubMed: 37693591
DOI: 10.1101/2023.08.30.555563 -
European Journal of Paediatric... Nov 2023Angelman Syndrome (AS) is a rare, severe neurogenetic disorder that causes symptoms such as intellectual disability and motor impairments and is typically diagnosed in...
PURPOSE
Angelman Syndrome (AS) is a rare, severe neurogenetic disorder that causes symptoms such as intellectual disability and motor impairments and is typically diagnosed in early childhood. The complexity and heterogeneity of AS confound characterization of disease severity and pose unique challenges when determining an individual's response to treatment. There is therefore a substantial unmet need for rating scales specifically designed for complex conditions such as AS. To address this, the Clinical Global Impressions (CGI) scale, which has components for both symptom severity (CGI-S) and improvement (CGI-I) was specifically adapted to measure severity (CGI-S-AS) and improvement (CGI-I-AS) in AS.
METHODS
The modified CGI-S/I-AS was used in the NEPTUNE trial of gaboxadol for the treatment of AS. Here we report on the validation of the CGI-I-AS using data from NEPTUNE and discuss insights for its potential use in future trials.
RESULTS
Improvements in the CGI-I-AS rating tended to be consistent with changes on other relevant rating scales. Sleep-related symptoms were particularly well represented, while communication-related symptoms were not.
CONCLUSIONS
Our validation analysis of the CGI-I-AS demonstrates its usefulness along with possible areas of improvement. The CGI-I-AS is a potential tool for use in other trials of AS drug candidates, and the process for its development can serve as a road map for the development of assessment tools for other neuropsychiatric disorders with similar complexities and heterogeneity.
Topics: Child, Preschool; Humans; Angelman Syndrome; Psychiatric Status Rating Scales; Severity of Illness Index; Treatment Outcome; Clinical Trials as Topic
PubMed: 37688937
DOI: 10.1016/j.ejpn.2023.08.003 -
European Journal of Paediatric... Nov 2023To evaluate efficacy and safety of gaboxadol for treatment of children with Angelman syndrome (AS). (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To evaluate efficacy and safety of gaboxadol for treatment of children with Angelman syndrome (AS).
METHOD
In this international, double-blind, phase 3 trial, we randomized children 4-12 years old with a molecular diagnosis of AS and a Clinical Global Impression (CGI)-severity score ≥3 to either daily administration of weight-based gaboxadol or matching placebo for 12 weeks. The primary endpoint was the CGI-Improvement-AS (CGI-I-AS) score at week 12. Secondary endpoints included the proportion of participants with CGI-I-AS response of ≤3 (i.e., at least "minimal improvement") and ≤2 (i.e., at least "much improvement") at week 12. Safety and tolerability were monitored throughout the study. Weight based dosing of study drug ranged from 0.125 mg/kg to 0.24 mg/kg depending on weight range.
RESULTS
Between August 2019 and November 2020, 104 participants were enrolled: participants 4-12 years old were randomly (1:1) assigned to gaboxadol (n = 47) or placebo (n = 50), and 7 other participants 2─3 years old who received gaboxadol and were assessed for safety only. All gaboxadol-treated participants and 48 of 50 placebo-treated participants completed treatment. There was no significant difference in CGI-I-AS between groups: at week 12, mean CGI-I-AS score was 3.3 (SD, 1.00) and 3.2 (SD, 1.05) in the gaboxadol and placebo groups, respectively, yielding a least squares mean difference of zero (p = 0.83). There were no between-group significant differences with respect to CGI-I-AS responses. Gaboxadol was well tolerated in all age groups of this study.
CONCLUSIONS
There was no significant difference in CGI-I-AS between gaboxadol and placebo after 12 weeks of study treatment in pediatric AS participants.
CLINICALTRIALS
GOV: NCT04106557.
Topics: Child; Child, Preschool; Humans; Angelman Syndrome; Double-Blind Method; Isoxazoles; Treatment Outcome
PubMed: 37639777
DOI: 10.1016/j.ejpn.2023.07.008 -
BioRxiv : the Preprint Server For... Aug 2023Aberrant BDNF signaling has been proposed to contribute to the pathophysiology of depression and other neurological disorders such as Angelman syndrome. We have...
Aberrant BDNF signaling has been proposed to contribute to the pathophysiology of depression and other neurological disorders such as Angelman syndrome. We have previously shown that targeting the TrkB / PSD-95 nexus by peptidomimetic inhibitors is a promising approach for therapeutic intervention. Here we used structure-based knowledge to develop a new peptidomimetic compound series that fuses SynGAP-derived peptides to our prototype compound CN2097. These compounds target the PSD-95 PDZ3 domain and adjoining αC helix to achieve bivalent binding that results in up to 7-fold stronger affinity compared to CN2097. These compounds were designed to improve CN2097 specificity for the PDZ3 domain and limited SAR studies have been performed to improve their resistance to proteolysis.
PubMed: 37609345
DOI: 10.1101/2023.08.10.552828 -
Expert Review of Neurotherapeutics 2023Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, limited expressive language, epilepsy, and motor impairment. Angelman... (Review)
Review
INTRODUCTION
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, limited expressive language, epilepsy, and motor impairment. Angelman syndrome is caused by haploinsufficiency of the UBE3A gene on the maternal copy of chromosome 15. There have been ongoing advances in the understanding of neurological, behavioral, and sleep-based problems and associated treatments for patients with AS. These results along with gene-based therapies entering into clinical development prompted this review.
AREAS COVERED
The authors summarize the research basis describing phenomenology of epilepsy and behavioral concerns such as hyperactivity behavior, aggression, self-injury, repetitive behavior, and sleep disorder. The evidence for recent treatment advances in these target symptom domains of concern is reviewed, and the potential for emerging gene therapy treatments is considered.
EXPERT OPINION
The prospect for emerging gene therapies means that increasing efforts should be directed toward the early identification of AS implemented equitably. Recent studies emphasize the important role of behavioral therapy in addressing mental health concerns such as aggression and disordered sleep.
Topics: Humans; Angelman Syndrome; Cognition; Aggression; Behavior Therapy; Epilepsy
PubMed: 37599585
DOI: 10.1080/14737175.2023.2245568 -
Behavioral Sleep Medicine 2024Angelman syndrome (AS) is a rare genetic developmental disability that presents with high rates of co-occurring sleep difficulties. Most existing research has focused on...
Angelman syndrome (AS) is a rare genetic developmental disability that presents with high rates of co-occurring sleep difficulties. Most existing research has focused on the pathophysiology of sleep problems in people with AS, and suggests that sleep problems are the result of genetic and neurobiological factors. However, little is known about the role of the social environment and learning in sleep problems in children with AS. This descriptive study used survey data from 139 parents of children with AS to investigate: 1) the type, topography and severity of children's sleep problems; 2) the collateral child, parent and family impacts of the sleep problems; 3) treatment selection practices and the perceived effectiveness of these treatments; and 4) sources of support and treatment advice received. Parents reported that the majority of children experienced sleep problems, resulting in numerous deleterious effects on child and family functioning. They also reported high levels of concern about these sleep problems, but low levels of perceived support. Study findings highlight the need to establish a disability-specific profile of the type and impact of sleep problems experienced by children with AS, and have further implications for the delivery of clinical services and support provided to parents of children with AS.
Topics: Humans; Angelman Syndrome; Male; Female; Child; Parents; Sleep Wake Disorders; Child, Preschool; Severity of Illness Index; Adolescent; Help-Seeking Behavior; Adult; Surveys and Questionnaires
PubMed: 37592732
DOI: 10.1080/15402002.2023.2241943 -
Journal of Autism and Developmental... Aug 2023In the current study, we examined adaptive skills and trajectories over time in 257 individuals with Angelman syndrome (AS) using the Vineland Adaptive Behavior Scales,...
In the current study, we examined adaptive skills and trajectories over time in 257 individuals with Angelman syndrome (AS) using the Vineland Adaptive Behavior Scales, 2nd Edition. Multilevel linear models were used to examine differences between molecular subtypes over time, from one year to 13 years of age, in the adaptive domains of communication, daily living skills, socialization and motor skills. Individuals with non-deletion subtypes typically demonstrated a higher level of adaptive skills compared to those with deletion subtypes. Statistically significant growth was observed in all adaptive domains through at least early adolescence. Individuals with AS should continue to receive developmental services and educational supports through adolescence and into adulthood given the slow rates of growth being observed across adaptive domains.
PubMed: 37581718
DOI: 10.1007/s10803-023-06090-8 -
Sleep Medicine Oct 2023
Topics: Humans; Angelman Syndrome; Sleep
PubMed: 37574611
DOI: 10.1016/j.sleep.2023.08.005