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Introduction:
Mechanistic target of rapamycin (mTOR) inhibitors sirolimus and everolimus are an effective therapy for subependymal giant cell astrocytomas, cardiac rhabdomyomas, renal angiomyolipomas, and lymphangioleiomyomatosis associated with tuberous sclerosis complex (TSC). Everolimus was recently approved in the EU and the USA for the treatm...
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Tuberous sclerosis complex (TSC) is a rare inherited disease with the potential to affect virtually every organ system. Clinical presentation is age- and partly sex-dependent and varies broadly with respect to disease manifestations including treatment-refractory epilepsy, intellectual disability and TSC-associated neuropsychiatric disorders, chron...
Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by seizures, neuropsychiatric disorders, and tumors of the heart, brain, skin, lungs, and kidneys. We present a three-year follow-up of a patient with TSC-associated rhabdomyoma detected in utero. Genetic examination of the fetus and the parents revealed a de novo variant in t...
Tuberous sclerosis (TS) is a potentially severe medical disorder that poses a life-threatening risk and can lead to drastic lifestyle changes. In infants and young children, the typical diagnostic criteria for this condition encompass cutaneous manifestations and seizures, and the development of cellular growths termed hamartomas, astrocytomas, myo...
It is extremely rare to encounter primary malignant tumors of the heart. Rhabdomyoma constitutes approximately 20% of all primary malignant tumors of the heart. Rhabdomyoma commonly arises from the ventricular wall, and rarely, they arise from the atrial wall and mimic symptomatic atrioventricular valve stenosis. We describe an extremely rare case...
Purpose
Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder that affects multiple organ systems. Mutations in the TSC1 and TSC2 genes result in the constitutive hyperactivation of the mammalian target of rapamycin (mTOR) pathway, contributing to the growth of benign tumors or hamartomas in various organs. Due to the impli...
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... Se encuentran en estudio los inhibidores mTOR para la prevención y tratamiento de epilepsia en niños con CET (18) , lo cual aumenta la importancia en hacer el diagnóstico temprano de tuberosis esclerosa, en especial en la población asintomática. ...
El complejo esclerosis tuberosa (CET) se caracteriza por desarrollar hamartomasen diversos tejidos. Se presenta el caso de una paciente de 39 años con feto conmúltiples rabdomiomas en quien se realizó diagnóstico prenatal molecular de CET.Con el diagnóstico confirmado se amplió la evaluación en el posnatal, encontrándosemáculas hipopigmentadas en piel y múltiples túberes corticales y subependimarios.En la evaluación familiar, el padre presentó lesiones cutáneas y está en estudiopara confirmar CET. A los 6 meses de vida, la lactante permanece asintomática. Eldiagnóstico de CET prenatal tiene un impacto en el pronóstico del paciente y sufamilia. Mejora el pronóstico neurológico posnatal, permite extender la búsquedade la enfermedad a padres y hermanos, aporta herramientas para consejería másprecisa del embarazo y planificación familiar.
... mTOR is mechanistically tightly interconnected with the TSC1/TSC2 complex; therefore, it has been found upregulated in patients with TSC-an autosomal dominant disorder caused by loss-of-function mutations of either TSC1 or TSC2 genes-who develop neurological manifestations, including epilepsy, neuropsychiatric disorders, autism, and brain tumors [20,21]. mTOR inhibition in TSC patients is promising against epilepsy, whereas mTORC1-associated autophagy has been correlated with neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease [22][23][24]. mTOR signaling is also engaged in the regulation of cardiac physiology and corresponding cardiovascular maladies. These include pulmonary arterial hypertension, myocardial infarction, and atherosclerosis [14]. ...
In the intricate landscape of human biology, the mechanistic target of rapamycin (mTOR) emerges as a key regulator, orchestrating a vast array of processes in health and disease [...]
... Apparent overactivation of mTOR signalling is prevalent in multiple types of epilepsy, including those resulting from genetic defects or acquired trauma [50,51]. Mutations in different regions of the mTOR pathway can lead to the development of epilepsy, and taking mTOR inhibitors reduces the number of seizures [52]. This is supported by the fact that suppression of mTOR signalling leads to a reduction in seizure frequency in patients with a mutation in TSC [53], STE20-related kinase adaptor protein α (STRADα) [54] and Rags1 [55]. ...
Simple Summary
Patients with gliomas experience worsened quality of life due to epileptic attacks. Over 80% of patients are susceptible to seizures, significantly hindering their treatment and well-being. No cause of epilepsy associated with glioma has been identified; however, some mutations are known to contribute to seizures in various situations. The development of a tumour creates advantageous conditions for abnormal neuronal activity to occur. Identifying a therapeutic target is a significant undertaking that numerous studies are endeavouring to undertake. We investigate the potential correlation of pathophysiological processes in the development of both gliomas and epilepsy, aiming to identify any shared factors. Furthermore, we propose that the mutational profile of different types of gliomas may have an impact on the occurrence or absence of seizures. We conclude that spontaneous neuronal activity arises from both the tumour microenvironment and blood ingress into neuronal networks resulting from the breakdown of the blood–brain barrier.
Abstract
Approximately 30% of glioma patients are able to survive beyond one year postdiagnosis. And this short time is often overshadowed by glioma-associated epilepsy. This condition severely impairs the patient’s quality of life and causes great suffering. The genetic, molecular and cellular mechanisms underlying tumour development and epileptogenesis remain incompletely understood, leading to numerous unanswered questions. The various types of gliomas, namely glioblastoma, astrocytoma and oligodendroglioma, demonstrate distinct seizure susceptibility and disease progression patterns. Patterns have been identified in the presence of IDH mutations and epilepsy, with tumour location in cortical regions, particularly the frontal lobe, showing a more frequent association with seizures. Altered expression of TP53, MGMT and VIM is frequently detected in tumour cells from individuals with epilepsy associated with glioma. However, understanding the pathogenesis of these modifications poses a challenge. Moreover, hypoxic effects induced by glioma and associated with the HIF-1a factor may have a significant impact on epileptogenesis, potentially resulting in epileptiform activity within neuronal networks. We additionally hypothesise about how the tumour may affect the functioning of neuronal ion channels and contribute to disruptions in the blood–brain barrier resulting in spontaneous depolarisations.
Epilepsy remains a major health concern as anti-seizure medications frequently fail, and there is currently no treatment to stop or prevent epileptogenesis, the process underlying the onset and progression of epilepsy. The identification of the pathological processes underlying epileptogenesis is instrumental to the development of drugs that may prevent the generation of seizures or control pharmaco-resistant seizures, which affect about 30% of patients. mTOR signalling and neuroinflammation have been recognized as critical pathways that are activated in brain cells in epilepsy. They represent a potential node of biological convergence in structural epilepsies with either a genetic or an acquired aetiology. Interventional studies in animal models and clinical studies give strong support to the involvement of each pathway in epilepsy. In this Review, we focus on available knowledge about the pathophysiological features of mTOR signalling and the neuroinflammatory brain response, and their interactions, in epilepsy. We discuss mitigation strategies for each pathway that display therapeutic effects in experimental and clinical epilepsy. A deeper understanding of these interconnected molecular cascades could enhance our strategies for managing epilepsy. This could pave the way for new treatments to fill the gaps in the development of preventative or disease-modifying drugs, thus overcoming the limitations of current symptomatic medications.
The mammalian/mechanistic target of rapamycin (mTOR) is a protein kinase that plays a crucial role in regulating cellular growth, metabolism, and survival. Although there is no absolute contraindication for the use of mTOR inhibitors during pregnancy, the specific fetal effects remain unknown. Available data from the past 2 decades have examined the use of mTOR inhibitors during pregnancy in patients with solid organ transplantation, showing no clear link to fetal complications or structural abnormalities. Recently, a handful of case reports and series have described transplacental therapy of mTOR inhibitors to control symptomatic and complicated pathologies in the fetus. The effect of these agents includes a significant reduction in lesion size in the fetus and a reduced need for mechanical ventilation in neonates. In this context, we delve into the potential of mTOR inhibitors as in‐utero therapy for fetal abnormalities, with a primary focus on lymphatic malformation (LM) and cardiac rhabdomyoma (CR). While preliminary reports underscore the efficacy of mTOR inhibitors for the treatment of fetal CR and fetal brain lesions associated with tuberous sclerosis complex, chylothorax, and LMs, additional investigation and clinical trials are essential to comprehensively assess the safety and efficacy of these medications.
The mammalian target of rapamycin (mTOR) is a protein kinase that controls cellular metabolism, catabolism, immune responses,autophagy, survival, proliferation, and migration, to maintain cellular homeostasis. The mTOR signaling cascade consists of twodistinct multi-subunit complexes named mTOR complex 1/2 (mTORC1/2). mTOR catalyzes the phosphorylation of several criticalproteins like AKT, protein kinase C, insulin growth factor receptor (IGF-1R), 4E binding protein 1 (4E-BP1), ribosomal protein S6kinase (S6K), transcription factor EB (TFEB), sterol-responsive element-binding proteins (SREBPs), Lipin-1, and Unc-51-likeautophagy-activating kinases. mTOR signaling plays a central role in regulating translation, lipid synthesis, nucleotide synthesis,biogenesis of lysosomes, nutrient sensing, and growth factor signaling. The emerging pieces of evidence have revealed that theconstitutive activation of the mTOR pathway due to mutations/amplification/deletion in either mTOR and its complexes (mTORC1and mTORC2) or upstream targets is responsible for aging, neurological diseases, and human malignancies. Here, we provide thedetailed structure of mTOR, its complexes, and the comprehensive role of upstream regulators, as well as downstream effectors ofmTOR signaling cascades in the metabolism, biogenesis of biomolecules, immune responses, and autophagy. Additionally, wesummarize the potential of long noncoding RNAs (lncRNAs) as an important modulator of mTOR signaling. Importantly, we havehighlighted the potential of mTOR signaling in aging, neurological disorders, human cancers, cancer stem cells, and drug resistance.Here, we discuss the developments for the therapeutic targeting of mTOR signaling with improved anticancer efficacy for thebenefit of cancer patients in clinics.
The capacity to integrate complex sensory cues and to coordinate an adequate behavioral response often requires integration of information within the outermost part of the mammalian brain called the cerebral cortex. The laminar and columnar cytoarchitecture of the cerebral cortex contains neurons that establish proximal and distal connections. Genetically encoded transcription factors ensure the generation of the appropriate number, types, locations, and connections of cortical neurons. However, somatic mutations that alter cortical development provide evidence that post-transcriptional regulation is equally important. An example is that somatic mutations in regulators and substrates of mammalian target of rapamycin (mTOR) are associated with neuropsychiatric and neurological manifestations. mTOR is a protein kinase that phosphorylates substrates that control mRNA translation and anabolic processes. Numerous challenges remain in uncovering the mechanisms by which mutations in regulators and substrates of mTOR impact behavior. Here, evidence is provided that somatic mosaicism can be modeled in the developing murine cerebral cortex which may have clinical significance.
Tuberous sclerosis complex is an autosomal dominant disease characterised by abnormal cell proliferation and differentiation that affects multiple organs and can lead to the growth of hamartomas. Tuberous sclerosis complex is caused by the disinhibition of the protein mTOR (mammalian target of rapamycin). In the past, various therapeutic approaches, even if only symptomatic, have been attempted to improve the clinical effects of this disease. While all of these therapeutic strategies are useful and are still used and indicated, they are symptomatic therapies based on the individual symptoms of the disease and therefore not fully effective in modifying long-term outcomes. A new therapeutic approach is the introduction of allosteric inhibitors of mTORC1, which allow restoration of metabolic homeostasis in mutant cells, potentially eliminating most of the clinical manifestations associated with Tuberous sclerosis complex. Everolimus, a mammalian target of the rapamycin inhibitor, is able to reduce hamartomas, correcting the specific molecular defect that causes Tuberous sclerosis complex. In this review, we report the findings from the literature on the use of everolimus as an effective and safe drug in the treatment of TSC manifestations affecting various organs, from the central nervous system to the heart.
