Defining the Role of Autophagy Kinase ULK1 Signaling in Therapeutic Response of Tuberous Sclerosis Complex to mTOR Inhibitors

2014 ◽  
Author(s):  
Reuben J. Shaw
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Therapeutic Response ◽  
Mtor Inhibitors

scholarly journals The effect of sirolimus on angiomyolipoma is determined by decrease of fat-poor compartments and includes striking reduction of vascular structures

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Elieser Hitoshi Watanabe ◽  
Fernando Morbeck Almeida Coelho ◽  
Hilton Leão Filho ◽  
Bruno Eduardo Pedroso Balbo ◽  
Precil Diego Miranda de Menezes Neves ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Blood Vessels ◽  
Tuberous Sclerosis Complex ◽  
Hounsfield Unit ◽  
Mtor Inhibitors ◽  
Volume Reduction ◽  
Tumor Reduction ◽  
Vascular Structures ◽  
Remarkable Reduction

AbstractRenal angiomyolipomas hemorrhage is associated with their size and vascular constitution. The effects of sirolimus on different components of angiomyolipomas was analyzed in patients with tuberous sclerosis complex, sporadic lymphangioleiomyomatosis and multiple sporadic angiomyolipomas. Thirty angiomyolipomas from 14 patients treated with sirolimus were retrospectively evaluated. A Hounsfield-unit threshold was used to classify angiomyolipomas in fat-rich, fat-poor and intermediate-fat tumors, and to categorize tumor compartments in fat rich, fat poor, intermediate fat and highly vascularized. Diameter variations were measured to assess the effects on aneurysmatic/ectatic vascular formations. Volume reduction following treatment with sirolimus was higher in fat-poor than fat-rich angiomyolipomas. Tumor reduction was mainly determined by decrease of the fat-poor and highly-vascularized compartments while the volume of the fat-rich compartment increased. Broad liposubstitution was observed in some tumors. A median reduction of 100% (75 to 100) in the diameter of aneurysmatic/ectatic vascular structures was observed. Our study showed that sirolimus reduces the size of angiomyolipomas by decreasing primarily their highly-vascularized and fat-poor compartments. This effect is associated with a remarkable reduction of tumoral aneurysms/ectatic vessels, revealing the likely mechanism responsible for the risk-decreasing effect of mTOR inhibitors on angiomyolipoma bleeding. These findings support the role of mTOR in the development of angiomyolipoma blood vessels.

The Role of mTOR Inhibitors in the Treatment of Patients with Tuberous Sclerosis Complex: Evidence-based and Expert Opinions

Drugs ◽  
2016 ◽  
Vol 76 (5) ◽  
pp. 551-565 ◽  
Author(s):  
Paolo Curatolo ◽  
Marit Bjørnvold ◽  
Patricia E. Dill ◽  
José Carlos Ferreira ◽  
Martha Feucht ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Mtor Inhibitors ◽  
Evidence Based ◽  
Expert Opinions

scholarly journals Recent advances in the management of lymphangioleiomyomatosis

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 758 ◽  
Author(s):  
Kai-Feng Xu ◽  
Xinlun Tian ◽  
Jay H Ryu
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Mtor Inhibitors ◽  
Rare Disorder ◽  
Mtor Signaling Pathway ◽  
Recent Advances ◽  
Function Impairment ◽  
Cystic Changes ◽  
Lung Function Impairment

Lymphangioleiomyomatosis is a rare disorder that predominantly affects women and is characterized by progressive cystic changes in the lung, leading to gradually worsening shortness of breath and lung function impairment. Pleural complications such as pneumothorax and chylothorax commonly occur in these patients. Lymphangioleiomyomatosis can occur as a form of lung involvement in tuberous sclerosis complex or as a sporadic form (without tuberous sclerosis complex). Etiology in both forms of this disease centers on mutations in the tuberous sclerosis genes. Advances in our understanding of the regulatory role of tuberous sclerosis gene products (hamartin/tuberin) in the mechanistic target of rapamycin (mTOR) signaling pathway have led to the identification of effective therapy (mTOR inhibitors) for a rare disorder, once considered uniformly fatal. Here, we summarize the evolution of current concepts regarding lymphangioleiomyomatosis with an emphasis on recent advances and unresolved issues.

scholarly journals The Putative Role of mTOR Inhibitors in Non-tuberous Sclerosis Complex-Related Epilepsy

2021 ◽  
Vol 12 ◽  
Author(s):  
Hannah E. Goldstein ◽  
Jason S. Hauptman
Keyword(s):  
Tuberous Sclerosis ◽  
Seizure Frequency ◽  
Tuberous Sclerosis Complex ◽  
Refractory Epilepsy ◽  
Mtor Inhibitors ◽  
Serine Threonine Kinase ◽  
Cortical Dysplasias ◽  
Highly Correlated ◽  
Medically Refractory Epilepsy

Epilepsy affects ~5 out of every 10,000 children per year. Up to one-third of these children have medically refractory epilepsy, with limited to no options for improved seizure control. mTOR, a ubiquitous 289 kDa serine/threonine kinase in the phosphatidylinositol 3-kinase (PI3K)-related kinases (PIKK) family, is dysregulated in a number of human diseases, including tuberous sclerosis complex (TSC) and epilepsy. In cell models of epilepsy and TSC, rapamycin, an mTOR inhibitor, has been shown to decrease seizure frequency and duration, and positively affect cell growth and morphology. Rapamycin has also been shown to prevent or improve epilepsy and prolong survival in animal models of TSC. To date, clinical studies looking at the effects of mTOR inhibitors on the reduction of seizures have mainly focused on patients with TSC. Everolimus (Novartis Pharmaceuticals), a chemically modified rapamycin derivative, has been shown to reduce seizure frequency with reasonable safety and tolerability. Mutations in mTOR or the mTOR pathway have been found in hemimegalencephaly (HME) and focal cortical dysplasias (FCDs), both of which are highly correlated with medically refractory epilepsy. Given the evidence to date, a logical next step is to investigate the role of mTOR inhibitors in the treatment of children with medically refractory non-TSC epilepsy, particularly those children who have also failed resective surgery.

scholarly journals Direct and indirect costs and cost-driving factors of Tuberous sclerosis complex in children, adolescents, and caregivers: a multicenter cohort study

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Janina Grau ◽  
Johann Philipp Zöllner ◽  
Susanne Schubert-Bast ◽  
Gerhard Kurlemann ◽  
Christoph Hertzberg ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Direct Cost ◽  
Nursing Care ◽  
Tuberous Sclerosis Complex ◽  
Indirect Costs ◽  
Mtor Inhibitors ◽  
Direct Costs ◽  
Driving Factors ◽  
Care Level ◽  
Organ Manifestations

Abstract Background Tuberous sclerosis complex (TSC), a multisystem genetic disorder, affects many organs and systems, characterized by benign growths. This German multicenter study estimated the disease-specific costs and cost-driving factors associated with various organ manifestations in TSC patients. Methods A validated, three-month, retrospective questionnaire was administered to assess the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket, and nursing care-level costs, completed by caregivers of patients with TSC throughout Germany. Results The caregivers of 184 patients (mean age 9.8 ± 5.3 years, range 0.7–21.8 years) submitted questionnaires. The reported TSC disease manifestations included epilepsy (92%), skin disorders (86%), structural brain disorders (83%), heart and circulatory system disorders (67%), kidney and urinary tract disorders (53%), and psychiatric disorders (51%). Genetic variations in TSC2 were reported in 46% of patients, whereas 14% were reported in TSC1. Mean total direct health care costs were EUR 4949 [95% confidence interval (95% CI) EUR 4088–5863, median EUR 2062] per patient over three months. Medication costs represented the largest direct cost category (54% of total direct costs, mean EUR 2658), with mechanistic target of rapamycin (mTOR) inhibitors representing the largest share (47%, EUR 2309). The cost of anti-seizure drugs (ASDs) accounted for a mean of only EUR 260 (5%). Inpatient costs (21%, EUR 1027) and ancillary therapy costs (8%, EUR 407) were also important direct cost components. The mean nursing care-level costs were EUR 1163 (95% CI EUR 1027–1314, median EUR 1635) over three months. Total indirect costs totaled a mean of EUR 2813 (95% CI EUR 2221–3394, median EUR 215) for mothers and EUR 372 (95% CI EUR 193–586, median EUR 0) for fathers. Multiple regression analyses revealed polytherapy with two or more ASDs and the use of mTOR inhibitors as independent cost-driving factors of total direct costs. Disability and psychiatric disease were independent cost-driving factors for total indirect costs as well as for nursing care-level costs. Conclusions This study revealed substantial direct (including medication), nursing care-level, and indirect costs associated with TSC over three months, highlighting the spectrum of organ manifestations and their treatment needs in the German healthcare setting. Trial registration: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045.

Clinical, cellular, and molecular characterisation of cardiac rhabdomyoma in tuberous sclerosis

2021 ◽  
pp. 1-9
Author(s):  
Hamood N. Al Kindi ◽  
Ayman M. Ibrahim ◽  
Mohamed Roshdy ◽  
Besra S. Abdelghany ◽  
Dina Yehia ◽  
...  
Keyword(s):  
Tuberous Sclerosis ◽  
Clinical Features ◽  
Tuberous Sclerosis Complex ◽  
Potential Role ◽  
Severe Disease ◽  
Cardiac Rhabdomyoma ◽  
Urgent Surgery ◽  
Pathogenic Mutations ◽  
Personalised Treatment

Abstract Background: Rhabdomyoma is the most common cardiac tumour in children. It is usually associated with tuberous sclerosis complex caused by mutations in TSC-1 or TSC-2 genes. This tumour typically regresses by unknown mechanisms; however, it may cause inflow or outflow obstruction that necessitates urgent surgery. Here we investigate the clinical features and the genetic analysis of patients with tuberous sclerosis complex presenting with large rhabdomyoma tumours. We also investigate the potential role of autophagy and apoptosis in the pathogenesis of this tumour. Methods: All the patients with cardiac rhabdomyoma referred to Aswan Heart Centre from 2010 to 2018 were included in this study. Sanger sequencing was performed for coding exons and the flanking intronic regions of TSC1 and TSC2 genes. Histopathological evaluation, immunohistochemistry, and western blotting were performed with P62, LC3b, caspase3, and caspase7, to evaluate autophagic and apoptotic signaling. Results: Five patients were included and had the clinical features of tuberous sclerosis complex. Three patients, who were having obstructive tumours, were found to have pathogenic mutations in TSC-2. The expression of two autophagic markers, P62 and LC3b, and two apoptotic markers, caspase3 and caspase7, were increased in the tumour cells compared to normal surrounding myocardial tissue. Conclusion: All the patients with rhabdomyoma were diagnosed to have tuberous sclerosis complex. The patients who had pathogenic mutations in the TSC-2 gene had a severe disease form necessitating urgent intervention. We also demonstrate the potential role of autophagy and apoptosis as a possible mechanism for tumourigenesis and regression. Future studies will help in designing personalised treatment for cardiac rhabdomyoma.

Genetic Etiologies, Diagnosis, and Treatment of Tuberous Sclerosis Complex

2019 ◽  
Vol 20 (1) ◽  
pp. 217-240 ◽  
Author(s):  
Catherine L. Salussolia ◽  
Katarzyna Klonowska ◽  
David J. Kwiatkowski ◽  
Mustafa Sahin
Keyword(s):  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Phenotypic Variability ◽  
Mtor Inhibitors ◽  
Multiple Organ ◽  
Great Promise ◽  
Optimal Timing ◽  
Autosomal Dominant Disorder ◽  
Organ Systems ◽  
Neuropsychiatric Manifestations

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems due to an inactivating variant in either TSC1 or TSC2, resulting in the hyperactivation of the mechanistic target of rapamycin (mTOR) pathway. Dysregulated mTOR signaling results in increased cell growth and proliferation. Clinically, TSC patients exhibit great phenotypic variability, but the neurologic and neuropsychiatric manifestations of the disease have the greatest morbidity and mortality. TSC-associated epilepsy occurs in nearly all patients and is often difficult to treat because it is refractory to multiple antiseizure medications. The advent of mTOR inhibitors offers great promise in the treatment of TSC-associated epilepsy and other neurodevelopmental manifestations of the disease; however, the optimal timing of therapeutic intervention is not yet fully understood.

Sign in / Sign up

Export Citation Format

Share Document