Article
Pediatrics
Katia Librandi, Serena Grimaldi, Silvia Catalano, Francesco Moro, Stefano Gabriele Vallero, Marco Spada, Francesco Porta
Summary: Tuberous sclerosis complex (TSC) is a rare multisystemic disorder that can include epilepsy as a common feature. This case report highlights the association between TSC and insulinomas, with the first pediatric case of a TSC patient diagnosed with an insulinoma. It emphasizes the importance of considering hypoglycemic events in TSC patients, especially in those with recurrent seizures previously controlled with antiepileptic therapy.
FRONTIERS IN PEDIATRICS
(2023)
Article
Cell Biology
Jiahuan Zhang, Song Xu, Kangyan Liang, Xiong Cao, Zhixin Ye, Wenlan Huang, Xiaochun Bai, Yue Zhang
Summary: This study generated a mouse model with conditional deletion of Tsc1 in Lyz2-positive cells, confirming the essential role of these cells in the pathological changes of TSC. These findings provide new insights into the role of Lyz2-positive neurons in TSC events.
CELLULAR SIGNALLING
(2022)
Article
Medicine, General & Internal
Marie Monaghan, Pooja Takhar, Luke Langlands, Markus Knuf, Sam Amin
Summary: Tuberous Sclerosis Complex (TSC) is a genetic condition that results in the loss of inhibition of cellular growth. Facial angiofibromas (FAs) are hamartomatous growths associated with TSC that appear as multiple small, erythematous papules on the skin of the face and may have psychosocial impacts such as anxiety and depression. A survey study found that FAs have an impact on quality of life and psychosocial well-being for TSC patients with moderate or severe FAs.
FRONTIERS IN MEDICINE
(2022)
Article
Clinical Neurology
Rima Nabbout, Elena Belousova, Mirjana P. Benedik, Tom Carter, Vincent Cottin, Paolo Curatolo, Maria Dahlin, Lisa D'Amato, Guillaume Beaure d'Augeres, Petrus J. de Vries, Jose C. Ferreira, Martha Feucht, Carla Fladrowski, Christoph Hertzberg, Sergiusz Jozwiak, John A. Lawson, Alfons Macaya, Ruben Marques, Finbar O'Callaghan, Jiong Qin, Matthias Sauter, Seema Shah, Yukitoshi Takahashi, Renaud Touraine, Sotiris Youroukos, Bernard Zonnenberg, Anna C. Jansen, J. Chris Kingswood
Summary: The study reveals a high prevalence of epilepsy and less severe epilepsy phenotypes associated with TSC1 mutations in TSC individuals. Vigabatrin is recommended as first-line treatment for infantile spasms, but further research is needed to improve therapies for focal seizures.
FRONTIERS IN NEUROLOGY
(2021)
Article
Neurosciences
Makiko Koike-Kumagai, Manabu Fujimoto, Mari Wataya-Kaneda
Summary: Tuberous sclerosis complex (TSC) is a genetic disorder associated with epilepsy and neuropsychiatric symptoms. This study successfully established a TAND model using TSC2 conditional knockout mice and found that changes in microglial polarity may be involved in the development of TSC epilepsy and neuropsychiatric symptoms. These findings contribute to the understanding of TAND pathogenesis and suggest sirolimus as a potential therapeutic tool for TAND.
Article
Clinical Neurology
Ji-Hye L. Hwang, Olga S. Perloff, Stephanie E. Gaus, Camila Benitez, Carolina Alquezar, Celica Q. Cosme, Alissa L. Nana, Sarat C. Vatsavayai, Eliana M. Ramos, Daniel H. Geschwind, Bruce L. Miller, Aimee W. Kao, William W. Seeley
Summary: This study found that individuals with tuberous sclerosis complex (TSC) are at risk for a unique age-related tauopathy. The tauopathy pathogenesis may involve TSC1, TSC2, and related molecular pathways.
ACTA NEUROPATHOLOGICA
(2023)
Article
Cell Biology
Ann-Sofie De Meulemeester, Lise Heylen, Aleksandra Siekierska, James D. Mills, Alessia Romagnolo, Nicole N. van der Wel, Eleonora Aronica, Peter A. M. de Witte
Summary: TSC is a genetic disorder caused by mutations in TSC1 and TSC2 genes. A double mutant zebrafish model was used to study the disease, and it was found that the double mutants had a more severe phenotype and could be rescued by rapamycin. The transcriptome of the double mutant zebrafish larvae strongly overlapped with human SEGA lesions.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Genetics & Heredity
Matthias Sauter, Elena Belousova, Mirjana P. Benedik, Tom Carter, Vincent Cottin, Paolo Curatolo, Maria Dahlin, Lisa D'Amato, Guillaume B. D'Augeres, Petrus J. de Vries, Jose C. Ferreira, Martha Feucht, Carla Fladrowski, Christoph Hertzberg, Sergiusz Jozwiak, John A. Lawson, Alfons Macaya, Ruben Marques, Rima Nabbout, Finbar O'Callaghan, Jiong Qin, Valentin Sander, Seema Shah, Yukitoshi Takahashi, Renaud Touraine, Sotiris Youroukos, Bernard Zonnenberg, Anna Jansen, J. Chris Kingswood
Summary: Rare manifestations and malignancies are relatively rare in patients with Tuberous sclerosis complex (TSC), but some rare symptoms and tumors are more common in adults. There is an association between TSC2 gene mutations and rare manifestations and malignancies.
ORPHANET JOURNAL OF RARE DISEASES
(2021)
Article
Clinical Neurology
Aglaia Vignoli, Francesca La Briola, Katherine Turner, Angela Peron, Chiara Vannicola, Valentina Chiesa, Elena Zambrelli, Fabio Bruschi, Ilaria Vigano, Maria Paola Canevini
Summary: In adults with tuberous sclerosis complex, the majority have epilepsy with about one-third achieving seizure freedom by age 18. The age of onset of epilepsy plays a crucial role in drug resistance and the development of intellectual disability. Drug-resistant patients are more likely to experience psychiatric disorders.
ACTA NEUROLOGICA SCANDINAVICA
(2021)
Review
Neurosciences
Tanjala T. Gipson, D. Kimbrough Oller, Daniel S. Messinger, Lynn K. Perry
Summary: Tuberous Sclerosis Complex (TSC) is a neurocutaneous disorder associated with a high prevalence of autism spectrum disorder (ASD), affecting around 50% of individuals. Understanding language development in individuals with TSC is crucial, as it may also have implications for those with other causes of syndromic and idiopathic ASD.
FRONTIERS IN HUMAN NEUROSCIENCE
(2023)
Article
Cell Biology
Muireann Ni Bhaoighill, Juan M. Falcon-Perez, Felix Royo, Andrew R. Tee, Jason P. Webber, Elaine A. Dunlop
Summary: This study investigates the role of extracellular vesicles (EVs) in modulating the tumor microenvironment and their impact on the development of TSC tumors. It shows that EVs secreted from TSC2-deficient cells contain a specific protein cargo that promotes cell viability, proliferation, and growth factor secretion in the tumor microenvironment. The study also demonstrates that rapamycin can alter the cargo of EVs and reduce their ability to promote cell proliferation.
JOURNAL OF EXTRACELLULAR VESICLES
(2023)
Review
Genetics & Heredity
Cong Luo, Wen-Rui Ye, Wei Shi, Ping Yin, Chen Chen, Yun-Bo He, Min-Feng Chen, Xiong-Bin Zu, Yi Cai
Summary: Tuberous sclerosis complex (TSC) is a genetic syndrome with diverse clinical features and organ dysfunction. The hyperactivation of the mTOR pathway is associated with most clinical manifestations in TSC. Although mTOR inhibitors show potential in TSC treatment, adverse events and poor response in some patients remain challenges. Thus, indicators are needed to predict the efficacy of mTOR inhibitors.
ORPHANET JOURNAL OF RARE DISEASES
(2022)
Review
Clinical Neurology
Tinghong Liu, Feng Chen, Feng Zhai, Shuli Liang
Summary: Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome, often associated with epilepsy. In China, research on surgical interventions for TSC patients has made significant progress.
ACTA NEUROLOGICA SCANDINAVICA
(2022)
Review
Medicine, General & Internal
Chao Gao, Bernadeta Zabielska, Fuyong Jiao, Daoqi Mei, Xiaona Wang, Katarzyna Kotulska, Sergiusz Jozwiak
Summary: Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder characterized by tumors in multiple organs, which is caused by mutations inactivating TSC1 or TSC2 genes. Subependymal giant cell astrocytoma (SEGA) is a slow-growing brain tumor almost exclusively associated with TSC. The management of SEGA requires careful consideration of pharmacological or surgical treatment options.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Anita Maasz, Timea Bodo, Agnes Till, Gabor Molnar, Gyoergy Masszi, Gusztav Labossa, Zsuzsanna Herbert, Judit Bene, Kinga Hadzsiev
Summary: "Impact of Early Genetic Testing and Antiepileptic Drug Therapy on Brain Development." This study presents a three-year follow-up of a patient with tuberous sclerosis complex (TSC) and a utero-detected rhabdomyoma. Genetic testing revealed a de novo variant in the TSC2 gene, and the pregnant mother was treated with everolimus to regress the fetal tumor. Early genetic testing, in utero treatment, and early medication intervention had a significant impact on the developmental delay of the patient.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Biographical-Item
Cell Biology
Michael Ristow, Chih-Hao Lee, Katrien De Bock, Vadim N. Gladyshev, Gokhan S. Hotamisligil, Brendan D. Manning
Article
Biology
Margaret E. Torrence, Michael R. MacArthur, Aaron M. Hosios, Alexander J. Valvezan, John M. Asara, James R. Mitchell, Brendan D. Manning
Summary: The study found that the mTORC1-ATF4 pathway activates a subset of ATF4 target genes induced by the ISR, including genes related to amino acid uptake, synthesis, and tRNA charging. ATF4 is identified as a metabolic effector of mTORC1, playing a role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.
Editorial Material
Oncology
Aaron M. Hosios, Brendan D. Manning
Summary: Research has deepened the understanding of oncogenic control of metabolism, particularly glycolysis. Current focus is on understanding the benefits and risks associated with glycolytic metabolism, and finding inhibitors that could be clinically beneficial for targeting glycolytic cancer cells.
Correction
Biochemistry & Molecular Biology
Andrew R. Tee, Brendan D. Manning, Philippe P. Roux, Lewis C. Cantley, John Blenis
Article
Endocrinology & Metabolism
Vanessa Byles, Yann Cormerais, Krystle Kalafut, Victor Barrera, James E. Hughes Hallett, Shannan Ho Sui, John M. Asara, Christopher M. Adams, Gerta Hoxhaj, Issam Ben-Sahra, Brendan D. Manning
Summary: The study demonstrates that ATF4 is stimulated by mTORC1 signaling in the liver in response to insulin during feeding, leading to changes in hepatocyte gene expression and metabolism. While insulin stimulates de novo purine and pyrimidine synthesis through mTORC1 signaling in primary hepatocytes, this regulation is independent of ATF4.
MOLECULAR METABOLISM
(2021)
Article
Multidisciplinary Sciences
Mona Hoseini Soflaee, Rushendhiran Kesavan, Umakant Sahu, Alpaslan Tasdogan, Elodie Villa, Zied Djabari, Feng Cai, Diem H. Tran, Hieu S. Vu, Eunus S. Ali, Halie Rion, Brendan P. O'Hara, Sherwin Kelekar, James Hughes Hallett, Misty Martin, Thomas P. Mathews, Peng Gao, John M. Asara, Brendan D. Manning, Issam Ben-Sahra, Gerta Hoxhaj
Summary: Purine depletion induces serine synthesis and promotes cancer cell migration and metastasis.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Sandra Schrotter, Christopher J. Yuskaitis, Michael R. MacArthur, Sarah J. Mitchell, Aaron M. Hosios, Maria Osipovich, Margaret E. Torrence, James R. Mitchell, Gerta Hoxhaj, Mustafa Sahin, Brendan D. Manning
Summary: TBC1D7 is an essential component of the TSC complex, which suppresses the growth of cells and tissues driven by mTORC1. In this study, Tbc1d7 knockout mice exhibited increased muscle fiber size, strength and motor defects, and overgrowth of the brain. These findings indicate that TBC1D7 is crucial for the full functionality of the TSC complex in tissues, with the brain being particularly sensitive to its growth-suppressing activities.
Article
Cell Biology
Christopher J. Yuskaitis, Jinita B. Modasia, Sandra Schrotter, Leigh-Ana Rossitto, Karenna J. Groff, Christopher Morici, Divakar S. Mithal, Ram P. Chakrabarty, Navdeep S. Chandel, Brendan D. Manning, Mustafa Sahin
Summary: Acute fasting can reduce seizure susceptibility in a DEPDC5-dependent manner through modulation of mTORC1 signaling and amino acid levels, suggesting a rational therapeutic strategy for epilepsy treatment.
Article
Multidisciplinary Sciences
Molly C. McNamara, Aaron M. Hosios, Margaret E. Torrence, Ting Zhao, Cameron Fraser, Meghan Wilkinson, David J. Kwiatkowski, Elizabeth P. Henske, Chin-Lee Wu, Kristopher A. Sarosiek, Alexander J. Valvezan, Brendan D. Manning
Summary: mTORC1 activation in cancer and TSC leads to cellular dependence on pro-survival proteins. Inhibiting mTORC1 alters this dependence, making cells more susceptible to apoptosis-inducing drugs.
Article
Endocrinology & Metabolism
Aaron M. Hosios, Meghan E. Wilkinson, Molly C. McNamara, Krystle C. Kalafut, Margaret E. Torrence, John M. Asara, Brendan D. Manning
Summary: Inhibition of mTORC1 leads to accumulation of intracellular triglycerides through lysosome-dependent hydrolysis of phospholipid fatty acids. The liberated fatty acids can be used for triglyceride synthesis or beta-oxidation.
Correction
Multidisciplinary Sciences
Andrew R. Tee, Diane C. Fingar, Brendan D. Manning, David J. Kwiatkowski, Lewis C. Cantley, John Blenis
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Meeting Abstract
Oncology
Brendan D. Manning
MOLECULAR CANCER RESEARCH
(2020)
Article
Medicine, Research & Experimental
Alexander J. Valvezan, Molly C. McNamara, Spencer K. Miller, Margaret E. Torrence, John M. Asara, Elizabeth P. Henske, Brendan D. Manning
Review
Oncology
Gerta Hoxhaj, Brendan D. Manning
NATURE REVIEWS CANCER
(2020)
Review
Endocrinology & Metabolism
Alexander J. Valvezan, Brendan D. Manning