Publications by authors named "Bebin E"
Objective: Tuberous sclerosis complex (TSC) results from overactivity of the mechanistic target of rapamycin (mTOR). Sirolimus and everolimus are mTOR inhibitors that treat most facets of TSC but are understudied in infants. We sought to understand the safety and potential efficacy of preventative sirolimus in infants with TSC.
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- The study investigates the relationship between early seizures and intellectual disability in children with tuberous sclerosis complex (TSC), focusing on how timing and frequency of seizures affect development.
- Researchers analyzed data from 129 TSC patients over 36 months, using machine learning to identify neurodevelopmental subgroups and effective biomarkers for predicting outcomes.
- Findings indicate that the total number of seizures (accumulated seizure burden) is a stronger predictor of cognitive development at 36 months than the age at which seizures begin, highlighting the importance of seizure management for better developmental outcomes.
Article Synopsis
- Long-read genome sequencing (lrGS) offers more accurate and comprehensive variant detection for rare diseases compared to short-read genome sequencing (srGS), though its exact impact on diagnostic yield remains unclear.
- In a study involving 96 individuals suspected of having genetic rare diseases, lrGS identified new or potentially relevant genetic variants in 16.7% of participants, with 9.4% possessing pathogenic or likely pathogenic variants.
- While lrGS provided additional insights beyond what was captured by srGS, particularly with structural variations, the study suggests that growing lrGS datasets will further enhance diagnostic capabilities in the future.
Members of the leucine rich repeat (LRR) and PDZ domain (LAP) protein family are essential for animal development and histogenesis. Densin-180, encoded by LRRC7, is the only LAP protein selectively expressed in neurons. Densin-180 is a postsynaptic scaffold at glutamatergic synapses, linking cytoskeletal elements with signalling proteins such as the α-subunit of Ca/calmodulin-dependent protein kinase II.
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- Children with tuberous sclerosis complex (TSC) have a high risk of developing drug-resistant epilepsy (DRE), making it crucial to identify those at greatest risk for timely management.
- The study analyzed data from 70 infants with TSC to evaluate the relationship between specific TSC genotypes and the likelihood of experiencing DRE, using a variety of statistical methods.
- Findings revealed that TSC2 pathogenic variants were strongly linked to DRE, with all DRE cases found in participants carrying TSC2 mutations; in contrast, TSC1 variants were associated with later-onset epilepsy, highlighting important differences in risk profiles.
Objective: The cannabidiol (CBD) Expanded Access Program provided compassionate access to CBD for patients with treatment-resistant epilepsy, including tuberous sclerosis complex (TSC), at 35 US epilepsy centers. Here, we present the long-term efficacy and safety outcomes for add-on CBD treatment in patients with TSC.
Methods: Patients received plant-derived, highly purified CBD (Epidiolex® 100 mg/mL, oral solution), increasing from 2 to 10 mg/kg/d to tolerance or maximum of 25-50 mg/kg/d.
Abnormalities in white matter development may influence development of autism spectrum disorder in tuberous sclerosis complex (TSC). Our goals for this study were as follows: (1) use data from a longitudinal neuroimaging study of tuberous sclerosis complex (TACERN) to develop optimized linear mixed effects models for analyzing longitudinal, repeated diffusion tensor imaging metrics (fractional anisotropy, mean diffusivity) pertaining to select white matter tracts, in relation to positive Autism Diagnostic Observation Schedule-Second Edition classification at 36 months, and (2) perform an exploratory analysis using optimized models applied to all white matter tracts from these data. Eligible participants (3-12 months) underwent brain magnetic resonance imaging (MRI) at repeated time points from ages 3 to 36 months.
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- Long-read genome sequencing (lrGS) outperforms short-read genome sequencing (srGS) in detecting genetic variants associated with rare diseases.
- In a study of 96 probands who tested negative with srGS, lrGS identified new disease-relevant variants in 16.7% of cases, with 8.33% containing pathogenic or likely pathogenic variants.
- lrGS revealed unique variants not detectable by srGS, highlighting that while reanalyzing previous data can improve diagnostic yield, lrGS provides significant additional insights into rare genetic conditions.
Common genetic variants identified in the general population have been found to increase phenotypic risks among individuals with certain genetic conditions. Up to 90% of individuals with tuberous sclerosis complex (TSC) are affected by some type of epilepsy, yet the common variants contributing to epilepsy risk in the general population have not been evaluated in the context of TSC-associated epilepsy. Such knowledge is important to help uncover the underlying pathogenesis of epilepsy in TSC which is not fully understood, and critical as uncontrolled epilepsy is a major problem in this population.
View Article and Find Full Text PDFObjective: This study was undertaken to test the hypothesis that early vigabatrin treatment in tuberous sclerosis complex (TSC) infants improves neurocognitive outcome at 24 months of age.
Methods: A phase IIb multicenter randomized double-blind placebo-controlled trial was conducted of vigabatrin at first epileptiform electroencephalogram (EEG) versus vigabatrin at seizure onset in infants with TSC. Primary outcome was Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) cognitive assessment score at 24 months.
Objective: The aim of this study was to assess potential drug-drug interactions between highly purified cannabidiol (CBD) and anti-seizure medications (ASMs).
Methods: Our group previously reported that in a sample of adults and children receiving CBD in an open-label expanded access program, there were several ASMs noted to increase in serum levels with increasing doses of CBD. We analyzed if an increased number of observations over time resulted in changes in potential interactions and if potential interactions were associated with time since enrollment, demographics, or the overall rating of adverse effects.
The cannabidiol (CBD) Expanded Access Program (EAP), initiated in 2014, provided CBD (Epidiolex) to patients with treatment-resistant epilepsy (TRE). In the final pooled analysis of 892 patients treated through January 2019 (median exposure = 694 days), CBD treatment was associated with a 46%-66% reduction in median monthly total (convulsive plus nonconvulsive) seizure frequency. CBD was well tolerated, and adverse events were consistent with previous findings.
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- Neurodevelopmental disorders (NDDs) are often linked to rare genetic variations, yet standard genomic testing misses many clinically relevant variants, prompting the need for alternative analyses like examining "poison exons" (PEs).
- The study involved curating RNA sequencing data to identify 1937 conserved PE regions relevant to NDDs and analyzing genetic variants across 2999 patients.
- The researchers discovered six novel relevant variants, mostly in genes associated with epilepsy, demonstrating that including PE analysis can enhance diagnostic yields for NDDs with minimal additional effort.
Background: Abnormal brain growth in tuberous sclerosis complex (TSC) reflects abnormalities in cellular proliferation and differentiation and results in epilepsy and other neurological manifestations. Head circumference (HC) as a proxy for brain volume may provide an easily tracked clinical measure of brain overgrowth and neurological disease burden. This study investigated the relationship between HC and epilepsy severity in infants with TSC.
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- Neurodevelopmental disorders (NDDs) can be linked to rare genetic variations, but standard genomic testing often misses key variants, particularly those in "poison exons" (PEs), which lead to premature termination of protein production.
- Researchers analyzed RNA sequencing data and identified 1,937 conserved PE regions to assess the impact of specific genetic variants in NDD cohorts.
- From nearly 3,000 individuals studied, six previously overlooked variants were found in PE regions that could explain certain NDDs, suggesting that including PE analysis could enhance diagnostic accuracy without significantly increasing the testing burden.
Objective: Tuberous sclerosis complex (TSC) is associated with focal brain "tubers" and a high incidence of autism spectrum disorder (ASD). The location of brain tubers associated with autism may provide insight into the neuroanatomical substrate of ASD symptoms.
Methods: We delineated tuber locations for 115 TSC participants with ASD (n = 31) and without ASD (n = 84) from the Tuberous Sclerosis Complex Autism Center of Excellence Research Network.
Background And Purpose: The success of epilepsy surgery in children with tuberous sclerosis complex (TSC) hinges on identification of the epileptogenic zone (EZ). We studied structural MRI markers of epileptogenic lesions in young children with TSC.
Methods: We included 26 children with TSC who underwent epilepsy surgery before the age of 3 years at five sites, with 12 months or more follow-up.
Purpose: Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed.
Methods: We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome.
Results: Computational facial and Human Phenotype Ontology-based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity.
Disruption of MeCP2-TCF20 complex underlies distinct neurodevelopmental disorders.
Proc Natl Acad Sci U S A
January 2022
Article Synopsis
- MeCP2 is linked to Rett syndrome and other conditions like autism and intellectual disabilities, but how it causes these diseases is still unclear.
- Researchers discovered that a protein complex involving TCF20 interacts with MeCP2, and mutations in MeCP2 disrupt this interaction, which can lead to disease.
- The study also shows that disruptions in the interactions between MeCP2 and the TCF20 complex can result in neurological issues, highlighting their importance for proper brain function.
Objective: To evaluate the long-term safety and efficacy of add-on cannabidiol (CBD) in patients with seizures associated with tuberous sclerosis complex (TSC) in the open-label extension (OLE) of the randomized, placebo-controlled phase 3 trial GWPCARE6 (NCT02544763). Results of an interim (February 2019 data cut) analysis are reported.
Methods: Patients who completed the randomized trial enrolled to receive CBD (Epidiolex in the United States; Epidyolex in the EU; 100 mg/mL oral solution).
In patients with treatment-resistant epilepsy (TRE), cannabidiol (CBD) produces variable improvement in seizure control. Patients in the University of Alabama at Birmingham CBD Expanded Access Program (EAP) were enrolled in the genomic study and genotyped using the Affymetrix Drug Metabolizing Enzymes and Transporters plus array. Associations between variants and CBD response (≥50% seizure reduction) and tolerability (diarrhea, sedation, and abnormal liver function) was evaluated under dominant and recessive models.
View Article and Find Full Text PDFBackground: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations.
View Article and Find Full Text PDFBackground: Epilepsy in tuberous sclerosis complex (TSC) typically presents with early onset, multiple seizure types, and intractability. However, variability is observed among individuals. Here, detailed individual data on seizure characteristics collected prospectively during early life were used to define epilepsy profiles in this population.
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