scholarly journals RHEB/mTOR hyperactivity causes cortical malformations and epileptic seizures through increased axonal connectivity

PLoS Biology ◽  
2021 ◽  
Vol 19 (5) ◽  
pp. e3001279
Author(s):  
Martina Proietti Onori ◽  
Linda M. C. Koene ◽  
Carmen B. Schäfer ◽  
Mark Nellist ◽  
Marcel de Brito van Velze ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Epileptic Seizures ◽  
Mtor Pathway ◽  
Vesicle Release ◽  
Generalized Seizures ◽  
Malformation Of Cortical Development ◽  
Physiological Abnormalities ◽  
Generalized Epilepsy ◽  
New Evidence ◽  
Focal Expression

Hyperactivation of the mammalian target of rapamycin (mTOR) pathway can cause malformation of cortical development (MCD) with associated epilepsy and intellectual disability (ID) through a yet unknown mechanism. Here, we made use of the recently identified dominant-active mutation in Ras Homolog Enriched in Brain 1 (RHEB), RHEBp.P37L, to gain insight in the mechanism underlying the epilepsy caused by hyperactivation of the mTOR pathway. Focal expression of RHEBp.P37L in mouse somatosensory cortex (SScx) results in an MCD-like phenotype, with increased mTOR signaling, ectopic localization of neurons, and reliable generalized seizures. We show that in this model, the mTOR-dependent seizures are caused by enhanced axonal connectivity, causing hyperexcitability of distally connected neurons. Indeed, blocking axonal vesicle release from the RHEBp.P37L neurons alone completely stopped the seizures and normalized the hyperexcitability of the distally connected neurons. These results provide new evidence of the extent of anatomical and physiological abnormalities caused by mTOR hyperactivity, beyond local malformations, which can lead to generalized epilepsy.

scholarly journals RHEB/mTOR-hyperactivity causing cortical malformations drives seizures through increased axonal connectivity

2020 ◽  
Author(s):  
Martina Proietti Onori ◽  
Linda M.C. Koene ◽  
Carmen B. Schafer ◽  
Mark Nellist ◽  
Marcel de Brito van Velze ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mammalian Target Of Rapamycin ◽  
Malformations Of Cortical Development ◽  
Cortical Malformation ◽  
Unknown Mechanism ◽  
Generalized Seizures ◽  
Physiological Abnormalities ◽  
Generalized Epilepsy ◽  
New Evidence ◽  
Focal Expression

ABSTRACTDominant-active mutations in Ras Homolog Enriched in Brain 1 (RHEB), such as the recently identified RHEBp.P37L mutation, can cause malformations of cortical development (MCD) with associated epilepsy and intellectual disability through a yet unknown mechanism. We found that focal expression of RHEBp.P37L in mouse somatosensory cortex results in an MCD-like phenotype, with increased mammalian target of rapamycin (mTOR) signaling, ectopic localization of neurons and generalized seizures. In addition, the RHEBp.P37L expressing neurons showed increased axonal length and branching. By temporally controlling RHEBp.P37L expression, we found that the cortical malformation by itself was neither necessary nor sufficient to generate seizures. Rather, seizures were contingent on persistent mTOR activation and enhanced axonal connectivity of RHEBp.P37L expressing neurons, causing hyperexcitability of distally connected neurons. These results provide new evidence of the extent of anatomical and physiological abnormalities caused by mTOR hyperactivity, beyond local malformations, that can lead to generalized epilepsy.

scholarly journals Epileptic events in the XIX century as reported by the Brazilian Royal Family

2010 ◽  
Vol 68 (3) ◽  
pp. 472-474
Author(s):  
Marleide da Mota Gomes ◽  
Heber de Souza Maia-Filho
Keyword(s):  
Medical Knowledge ◽  
Family Health ◽  
Epileptic Seizures ◽  
Febrile Convulsion ◽  
Royal Family ◽  
Generalized Seizures ◽  
History Of ◽  
Symptomatic Seizures ◽  
Generalized Epilepsy ◽  
Acute Symptomatic Seizures

Members of the Brazilian Royal Family carry a rich medical history of epileptic seizures and alike. OBJECTIVE: To present the medical knowledge about epilepsy by the time of the Brazilian Empire, as reported by the royal family. METHOD: Narrative review of historical facts about D. Pedro I's family health. RESULTS: The Royal Family, since D. João VI's generation is full of members with epilepsy or acute symptomatic seizures of different etiologies. CONCLUSION: The reported cases suggest that Dom Pedro I's family presented epilepsy with tonic-clonic generalized seizures, besides psychogenic, organic non epileptic events and acute symptomatic seizures. As a whole, this familial epilepsy could fit the diagnosis of generalized epilepsy with febrile convulsion plus.

Targeting mammalian target of rapamycin: prospects for the treatment of inflammatory bowel diseases

2020 ◽  
Vol 27 ◽  
Author(s):  
Naser-Aldin Lashgari ◽  
Nazanin Momeni Roudsari ◽  
Saeideh Momtaz ◽  
Negar Ghanaatian ◽  
Parichehr Kohansal ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Mtor Signaling ◽  
Target Of Rapamycin ◽  
In Vivo Studies ◽  
Cochrane Library ◽  
Mtor Signaling Pathway ◽  
Inflammatory Bowel

: Inflammatory bowel disease (IBD) is a general term for a group of chronic and progressive disorders. Several cellular and biomolecular pathways are implicated in the pathogenesis of IBD, yet the etiology is unclear. Activation of the mammalian target of rapamycin (mTOR) pathway in the intestinal epithelial cells was also shown to induce inflammation. This review focuses on the inhibition of the mTOR signaling pathway and its potential application in treating IBD. We also provide an overview on plant-derived compounds that are beneficial for the IBD management through modulation of the mTOR pathway. Data were extracted from clinical, in vitro and in vivo studies published in English between 1995 and May 2019, which were collected from PubMed, Google Scholar, Scopus and Cochrane library databases. Results of various studies implied that inhibition of the mTOR signaling pathway downregulates the inflammatory processes and cytokines involved in IBD. In this context, a number of natural products might reverse the pathological features of the disease. Furthermore, mTOR provides a novel drug target for IBD. Comprehensive clinical studies are required to confirm the efficacy of mTOR inhibitors in treating IBD.

scholarly journals Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung

2010 ◽  
Vol 17 (4) ◽  
pp. 977-987 ◽  
Author(s):  
Luisella Righi ◽  
Marco Volante ◽  
Ida Rapa ◽  
Veronica Tavaglione ◽  
Frediano Inzani ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Differential Sensitivity ◽  
Initiation Factor ◽  
Target Of Rapamycin ◽  
Low Grade ◽  
Mtor Inhibition ◽  
Signaling Activation ◽  
Activation Status

Among alternative therapeutic strategies in clinically aggressive neuroendocrine tumors (NETs) of the lung, promising results have been obtained in experimental clinical trials with mammalian target of rapamycin (mTOR) inhibitors, though in the absence of a proven mTOR signaling activation status. This study analyzed the expression of phosphorylated mTOR (p-mTOR) and its major targets, the ribosomal p70S6-kinase (S6K) and the eukaryotic initiation factor 4E-binding protein 1 (4EBP1) in a large series of 218 surgically resected, malignant lung NETs, including 24 metastasizing typical carcinoids, 73 atypical carcinoids, 60 large cell neuroendocrine carcinomas (LCNECs), and 61 small cell carcinomas (SCLCs). By immunohistochemistry, low-to-intermediate-grade tumors as compared with high-grade tumors showed higher levels of p-mTOR and phosphorylated S6K (p-S6K) (P<0.001), at variance with phosphorylated 4EBP1 (p-4EBP1), which was mainly expressed in LCNECs and SCLCs (P<0.001). The activated status of mTOR pathway was proved by the strong correlation of p-mTOR with p-S6K and somatostatin receptor(s). Western blot analysis of NET tumor samples confirmed such findings, and differential sensitivity to mTOR inhibition according to mTOR pathway activation characteristics was determined in two lung carcinoid cell lines in vitro. None of the investigated molecules had an impact on survival. However, in low-grade tumors, low p-mTOR expression correlated with lymph node metastases (P=0.016), recurrent disease, and survival (P=0.005). In conclusion, these data demonstrate a differential mTOR activation status in the spectrum of pulmonary NETs, possibly suggesting that mTOR pathway profiling might play a predictive role in candidate patients for mTOR-targeted therapies.

scholarly journals Etiology of epilepsy a prospective study of 210 cases

1991 ◽  
Vol 49 (3) ◽  
pp. 251-254 ◽  
Author(s):  
Walter Oleschko Arruda
Keyword(s):  
Ct Scan ◽  
Neurological Examination ◽  
Epileptic Seizures ◽  
Partial Seizures ◽  
Complex Partial Seizures ◽  
Blood Tests ◽  
Generalized Seizures ◽  
A Prospective Study ◽  
Csf Examination

The objective of this study was to establish the etiology of epilepsy in 210 chronic epileptics (110 female, 100 male), aged 14-82 years (34.2±13.3). Patients less than 10 years-old and alcoholism were excluded. All underwent neurological examination, routine blood tests, EEG and CT-scan. Twenty patients (10.5%) were submitted to spinal tap for CSF examination. Neurological examination was abnormal in 26 (12.4%), the EEG in 68 (45.5%), and CT-scan in 93 (44.3%). According to the International Classification of Epileptic Seizures (1981), 101 (48.1%) have generalized seizures, 66 (31.4%) partial seizures secondarily generalized, 25 (11.8%) simple partial and complex partial seizures, and 14 (6.6%) generalized and partial seizures. Four patients (2.0%) could not be classified. In 125 (59.5%) patients the etiology was unknown. Neurocysticercosis accounted for 57 (27.1%) of cases, followed by cerebrovascular disease 8 (3.8%), perinatal damage 5 (2.4%), familial epilepsy 4 (1.9%), head injury 4 (1.9%), infective 1 (0.5%), and miscelanea 6 (2.8%).

scholarly journals Juvenile myoclonic epilepsy: current state of the problem

2021 ◽  
Vol 1 (2) ◽  
pp. 2-20
Author(s):  
N. A. Shnayder ◽  
K. V. Petrov
Keyword(s):  
Primary Care Physicians ◽  
Epileptic Seizures ◽  
Juvenile Myoclonic Epilepsy ◽  
Historical Significance ◽  
Current State ◽  
High Prevalence ◽  
Clonic Seizures ◽  
Generalized Epilepsy ◽  
Genetically Determined ◽  
Selection Of

Due to the high prevalence of the disease, its genetic and clinical heterogeneity, the need for lifelong therapy and the emergence of new views on the pathogenesis and course of JME, it is necessary to provide primary care physicians (general practitioners, district therapists, neurologists) with up-to-date systematized information about the most common form of genetic generalized epilepsy (Herpin-Janz syndrome). JME is a genetically determined disease of the brain, accompanied by a triad of seizures (absences, myoclonia, generalized tonic-clonic seizures), and developing mainly in adolescence and young age. In recent years, monogenic and multifactorial forms of JME have been identified, but questions about the genetics of JME are far from being resolved. JME is characterized by the preservation of intelligence, life expectancy with adequate therapy does not differ from the average population, but the frequency of failures of pharmaco-induced remission is high when taking anticonvulsants is canceled. This explains the need for lifelong pharmacotherapy, individual selection of anticonvulsants. About 30% of patients with JME have non-psychotic mental disorders, disorders of the sleep and wake cycle, which in turn leads to an aggravation of epileptic seizures mainly in the first half of the day. This review presents an analysis of full-text publications in Russian and English over the past five years in the databases eLibrary, PubMed, Web of Science, OxfordPress, Springer, and Clinicalkeys. In addition, the review includes earlier publications of historical significance.

Medical Management in Focal versus Generalized Epilepsy

2021 ◽  
Vol 10 (02) ◽  
pp. 081-087
Author(s):  
Kumar Sannagowdara ◽  
Nadir Khan
Keyword(s):  
Broad Spectrum ◽  
Side Effect ◽  
Seizure Control ◽  
Therapeutic Effects ◽  
Side Effect Profile ◽  
Genetics Research ◽  
Generalized Seizures ◽  
Technological Advances ◽  
Generalized Epilepsy ◽  
New Compounds

AbstractAbout 70% of children with new-onset epilepsy have the potential to become seizure-free on antiepileptic drug (AED) monotherapy with appropriately selected first-line medication. In ideal world, physician is expected to achieve best possible seizure control without impacting the quality of life. There is rapid increase in number of AEDs available over last couple of decades. Although not necessarily all of them are superior to old generation drugs in terms of seizure control, certainly there is change in landscape from perspective of tolerability and side-effect profile. Physicians must therefore be familiar with safety, tolerability, therapeutic effects, synergistic combinations as well as AEDs to avoid in specific circumstances. The article attempts to give general overview of available AEDs under broad umbrella of effectiveness against focal and generalized seizures as well as drugs with “broad spectrum.” The emergence of newer AEDs with broad spectrum and favorable side-effect profile is welcome. However, the future lies in better understanding of underlying diverse pathophysiology of clinical symptom “epilepsy” and developing new compounds acting on molecular targets as well as individualizing therapy. Technological advances in molecular genetics research are bringing precision medicine to the fore.

Classification of seizures and epilepsy

2019 ◽  
pp. 935-944
Author(s):  
Andrew McEvoy ◽  
Tim Wehner ◽  
Victoria Wykes
Keyword(s):  
Focal Epilepsy ◽  
Focal Cortical Dysplasia ◽  
Hippocampal Sclerosis ◽  
Epileptic Seizures ◽  
Recurrence Risk ◽  
Medical Emergency ◽  
Unprovoked Seizure ◽  
Generalized Seizures ◽  
The Brain

Epileptic seizures are transient neurologic alterations due to abnormal excessive or synchronous neuronal cerebral activity. They may cause subjective symptoms (aura), and objective autonomic, behavioural, or cognitive alterations in any combination. Focal seizures are initially generated in one circumscribed area in the brain, whereas generalized seizures involve bihemispheric neuronal networks from the seizure onset. Epilepsy is a brain disease defined by the occurrence of two unprovoked seizures more than 24 h apart or one unprovoked seizure with underlying pathological or genetic factors resulting in a similar recurrence risk. Focal epilepsy syndromes are best classified by aetiology or anatomical area of origin. A seizure that does not self-terminate results in status epilepticus, and constitutes a medical emergency that requires immediate treatment. Focal cortical dysplasia and hippocampal sclerosis are the commonest aetiologies of epilepsy amenable to surgical treatment and are reviewed here. The limbic pathway may be involved in seizure propagation, and the anatomy is described.

scholarly journals Retention Rate and Efficacy of Perampanel with a Slow Titration Schedule in Adults

2020 ◽  
pp. 1-7
Author(s):  
Mazen Basheikh ◽  
R. Mark Sadler
Keyword(s):  
Seizure Frequency ◽  
Retention Rate ◽  
Responder Rate ◽  
Dose Titration ◽  
Seizure Freedom ◽  
Chart Audit ◽  
Generalized Seizures ◽  
Included Patient ◽  
Generalized Epilepsy

ABSTRACT: Rationale: The manufacturer of perampanel (PER) suggests an initial adult dose of 2–4 mg/day and an upward dose titration of 2 mg at no more frequently than 1- or 2-week intervals when used with enzyme-enhancing antiepileptic drugs (AEDs) or nonenzyme-enhancing AEDs, respectively. The general practice in our clinic is an initial dose of PER 2 mg/day and titrated by 2 mg/4 weeks to an initial target of 6 mg/day. Methods: Retrospective chart audit of patients starting PER in an adult epilepsy clinic between September 2013 and November 2016 with at least one 6-month follow-up visit was reviewed. Data collection included patient demographics, seizure characteristics, past and concurrent therapy, monthly seizure frequency before PER and at 6-month visit, and characteristics of PER discontinuation. Efficacy of treatment was assessed with the Engel classification and 50% responder rate. Results: N = 102 patients; mean age = 40 years and 54% females. Focal onset seizures 85%, generalized 13%, and unknown 2%. Median prior AED exposure = 6 (range 3–20); median concomitant AED use = 2 (range 1–5). Follow-up range was 6–37 months. The median seizure frequency/month prePER treatment was 6 (range 0–30) for focal onset seizures and 1 (range 0–6) for generalized seizures. The retention rate amongst all patients at 6 months was 78.4%. At 6-month follow-up, 36% of all patients achieved Engel class I (seizure freedom) (30.7% of patients with focal onset seizures and 63.6% with generalized epilepsy). The 50% responder rate was 52% and 82% for focal and generalized epilepsy, respectively. Conclusion: PER has a good retention rate when titrated slowly and thus encouraging seizure freedom results in an otherwise medically refractory epilepsy population.

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