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Journal of Neurosciences in Rural... 2024The profile of seizures in neurocutaneous syndromes is variable. We aimed to define the characteristics of epilepsy in children with neurocutaneous syndromes.
OBJECTIVES
The profile of seizures in neurocutaneous syndromes is variable. We aimed to define the characteristics of epilepsy in children with neurocutaneous syndromes.
MATERIALS AND METHODS
Cross-sectional study over 18 months at a tertiary care pediatric hospital, including children with neurocutaneous syndromes aged between 1 and 15 years, using the 2017-International League Against Epilepsy classification.
RESULTS
In 119 children with neurocutaneous syndromes, 94 (79%) had epilepsy. In eight children with neurofibromatosis one with epilepsy, 5 (62.5%) had generalized motor tonic-clonic seizures, 1 (12.5%) had generalized motor epileptic spasms, 1 (12.5%) had generalized motor automatism, and 1 (12.5%) had a focal seizure. In 69 children with tuberous sclerosis complex with epilepsy, 30 (43.5%) had generalized motor epileptic spasms, 23 (33.3%) had focal seizures, and nine (13.0%) had generalized motor tonic-clonic seizures. In 14 children with Sturge-Weber syndrome with epilepsy, 13 (92.8%) had focal seizures, and 1 (7.2%) had generalized motor tonic seizures. Statistically significant associations were found between epilepsy and intellectual disability ( = 0.02) and behavioral problems ( = 0.00).
CONCLUSION
Profiling seizures in children with neurocutaneous syndromes are paramount in devising target-specific treatments as the epileptogenesis in each syndrome differs in the molecular pathways leading to the hyperexcitability state. Further multicentric studies are required to unravel better insights into the epilepsy profile of neurocutaneous syndromes.
PubMed: 38746526
DOI: 10.25259/JNRP_510_2023 -
Research Square Apr 2024Most Epstein-Barr virus-associated gastric carcinoma (EBVaGC) harbor non-silent mutations that activate phosphoinositide 3 kinase (PI3K) to drive downstream metabolic...
Most Epstein-Barr virus-associated gastric carcinoma (EBVaGC) harbor non-silent mutations that activate phosphoinositide 3 kinase (PI3K) to drive downstream metabolic signaling. To gain insights into PI3K/mTOR pathway dysregulation in this context, we performed a human genome-wide CRISPR/Cas9 screen for hits that synergistically blocked EBVaGC proliferation together with the PI3K antagonist alpelisib. Multiple subunits of carboxy terminal to LisH (CTLH) E3 ligase, including the catalytic MAEA subunit, were among top screen hits. CTLH negatively regulates gluconeogenesis in yeast, but not in higher organisms. Instead, we identified that the CTLH substrates MKLN1 and ZMYND19, which highly accumulated upon MAEA knockout, associated with one another and with lysosomes to inhibit mTORC1. ZMYND19/MKLN1 bound Raptor and RagA/C, but rather than perturbing mTORC1 lysosomal recruitment, instead blocked a late stage of its activation, independently of the tuberous sclerosis complex. Thus, CTLH enables cells to rapidly tune mTORC1 activity at the lysosomal membrane via the ubiquitin/proteasome pathway.
PubMed: 38746323
DOI: 10.21203/rs.3.rs-4259395/v1 -
International Journal of Molecular... Apr 2024Tuberous sclerosis complex (TSC) presents with renal cysts and benign tumors, which eventually lead to kidney failure. The factors promoting kidney cyst formation in TSC...
Tuberous sclerosis complex (TSC) presents with renal cysts and benign tumors, which eventually lead to kidney failure. The factors promoting kidney cyst formation in TSC are poorly understood. Inactivation of carbonic anhydrase 2 ( significantly reduced, whereas, deletion of Foxi1 completely abrogated the cyst burden in KO mice. In these studies, we contrasted the ontogeny of cyst burden in dKO mice vs. dKO mice. Compared to KO, the dKO mice showed few small cysts at 47 days of age. However, by 110 days, the kidneys showed frequent and large cysts with overwhelming numbers of A-intercalated cells in their linings. The magnitude of cyst burden in dKO mice correlated with the expression levels of Foxi1 and was proportional to mTORC1 activation. This is in stark contrast to dKO mice, which showed a remarkable absence of kidney cysts at both 47 and 110 days of age. RNA-seq data pointed to profound upregulation of and kidney-collecting duct-specific H-ATPase subunits in 110-day-old dKO mice. We conclude that inactivation temporarily decreases the kidney cyst burden in KO mice but the cysts increase with advancing age, along with enhanced Foxi1 expression.
Topics: Animals; Mice; Mice, Knockout; Kidney Diseases, Cystic; Tuberous Sclerosis; Carbonic Anhydrase II; Forkhead Transcription Factors; Tuberous Sclerosis Complex 1 Protein; Gene Deletion; Kidney
PubMed: 38731991
DOI: 10.3390/ijms25094772 -
International Journal of Molecular... Apr 2024Colorectal cancer (CRC) is the second leading cause of cancer deaths globally. While ethnic differences in driver gene mutations have been documented, the South American... (Comparative Study)
Comparative Study
Colorectal cancer (CRC) is the second leading cause of cancer deaths globally. While ethnic differences in driver gene mutations have been documented, the South American population remains understudied at the genomic level, despite facing a rising burden of CRC. We analyzed tumors of 40 Chilean CRC patients (Chp) using next-generation sequencing and compared them to data from mainly Caucasian cohorts (TCGA and MSK-IMPACT). We identified 388 mutations in 96 out of 135 genes, with (45%), (30%), (22.5%), (20%), and (20%) being the most frequently mutated. mutations were associated with right colon cancer (44.44% in RCRC vs. 6.45% in LCRC, -value = 0.016), and overall frequency was higher compared to TCGA (-value = 1.847 × 10) and MSK-IMPACT cohorts (-value = 3.062 × 10). Limited sample size restricts definitive conclusions, but our data suggest potential differences in driver mutations for Chilean patients, being that the RTK-RAS oncogenic pathway is less affected and the PI3K pathway is more altered in Chp compared to TCGA (45% vs. 25.56%, respectively). The prevalence of actionable pathways and driver mutations can guide therapeutic choices, but can also impact treatment effectiveness. Thus, these findings warrant further investigation in larger Chilean cohorts to confirm these initial observations. Understanding population-specific driver mutations can guide the development of precision medicine programs for CRC patients.
Topics: Humans; Chile; Tuberous Sclerosis Complex 2 Protein; Mutation; Male; Female; Middle Aged; Colonic Neoplasms; Aged; Adult; High-Throughput Nucleotide Sequencing; Aged, 80 and over; Signal Transduction
PubMed: 38731914
DOI: 10.3390/ijms25094695 -
Molecules (Basel, Switzerland) Apr 2024It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat... (Review)
Review
It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat different types of seizures related to Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and more recently tuberous sclerosis complex (TSC). During this time, 39 randomized clinical trials (RCTs) and 13 meta-analyses on the efficacy and safety of CBD treatment have been published. Each of the meta-analyses had its own criteria for the RCTs' inclusion and, therefore, slightly different interpretations of the analyzed data. Each of them contributed in its own way to the understanding of CBD pharmacology, mechanisms of therapeutic action, development of adverse reactions, and drug-drug interactions. Hence, it seemed reasonable to gather the most relevant data in one article and present all the current knowledge on the use of CBD in epilepsy. The results of the 13 meta-analyses presented herein confirmed the effectiveness and safety of CBD in children and adolescents with DREs. In adults, reliable conclusions cannot be drawn due to insufficient data.
Topics: Humans; Cannabidiol; Epilepsy; Anticonvulsants; Randomized Controlled Trials as Topic; Lennox Gastaut Syndrome; Child; Treatment Outcome; Epilepsies, Myoclonic
PubMed: 38731471
DOI: 10.3390/molecules29091981 -
Saudi Journal of Kidney Diseases and... Nov 2023Renal angiomyolipomas (AMLs) and pulmonary lymphangioleiomyomatosis (LAM) are two major presentations of tuberous sclerosis (TS), an autosomal dominant multisystem...
Renal angiomyolipomas (AMLs) and pulmonary lymphangioleiomyomatosis (LAM) are two major presentations of tuberous sclerosis (TS), an autosomal dominant multisystem disorder. Renal AMLs can lead to life-threatening complications like hemorrhage and cause progressive renal failure requiring dialysis and kidney transplant. mTOR inhibitors showed promising results in TS patients with renal AMLs, LAM, and subependymal giant cell astrocytomas. This case report is a follow-up of a patient we reported in 2010 with giant AMLs and LAM who required an emergency nephrectomy for massive hemorrhage from giant left-sided AMLs.
Topics: Humans; Kidney Neoplasms; Angiomyolipoma; Lymphangioleiomyomatosis; Lung Neoplasms; Female; Nephrectomy; Tuberous Sclerosis; Adult; Treatment Outcome; Hemorrhage; Time Factors; Tumor Burden; Tomography, X-Ray Computed
PubMed: 38725217
DOI: 10.4103/sjkdt.sjkdt_324_21 -
SAGE Open Medical Case Reports 2024Tuberous sclerosis is an uncommon neurocutaneous syndrome characterized by hamartomatous growths with unpredictable progression. Diagnosing and managing neonatal...
Tuberous sclerosis is an uncommon neurocutaneous syndrome characterized by hamartomatous growths with unpredictable progression. Diagnosing and managing neonatal tuberous sclerosis can be challenging. We report a rare case of a 30-day-old male born out of a non-consanguineous marriage who presented with poor suckling and persistent abnormal body movement, required prolonged intensive care, and was diagnosed with tuberous sclerosis with multisystem involvement.
PubMed: 38715902
DOI: 10.1177/2050313X241252342 -
Neurology. Genetics Apr 2024Tuberous sclerosis complex (TSC) is a genetic disorder caused by a or gene variation characterized by widespread hamartomas in organs such as the skin, brain, heart,...
OBJECTIVES
Tuberous sclerosis complex (TSC) is a genetic disorder caused by a or gene variation characterized by widespread hamartomas in organs such as the skin, brain, heart, lungs, liver, and kidneys.
METHODS
We report a case of a patient with TSC who presented with broad clinical manifestations, including epilepsy.
RESULTS
An 18-year-old man was diagnosed with recurrent drug-resistant epilepsy. Neuroimaging revealed bilateral cortical and subcortical tubers with multiple calcified subependymal nodules. His skin involvement and psychomotor retardation raised the suspicion of TSC. Genetic testing confirmed the diagnosis, and a combined treatment including mTOR inhibitors was initiated.
DISCUSSION
TSC, although considered rare, needs to be considered when evaluating patients with broad clinical manifestations. Our report has significant implications for understanding the impact of genotype on the prognosis of TSC and the selection of treatment strategies for TSC-related refractory epilepsy.
PubMed: 38715652
DOI: 10.1212/NXG.0000000000200127 -
Acta Neuropathologica May 2024GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation-inhibition regulation, and cognitive function modulation. In tuberous...
GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation-inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal NKCC1/KCC2 ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABA receptor subunits, GABRA1, and upregulation of GABRA2. Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.
Topics: Interneurons; Tuberous Sclerosis; Humans; GABAergic Neurons; Male; Female; Median Eminence; Somatostatin; Child; Child, Preschool; Receptors, GABA-A; Adolescent; Ganglionic Eminence
PubMed: 38714540
DOI: 10.1007/s00401-024-02737-7