Tuberous sclerosis: a syndrome of incomplete tumor suppression

Tuberous sclerosis (TS) is a congenital neurocutaneous syndrome (or phacomatosis) characterized by widespread development of hamartomas in multiple organs. For affected individuals, neurological and psychiatric complications are the most disabling and lethal features. Although the clinical phenotype of TS is complex, only three lesions characterize the neuropathological features of the disease: cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas. The latter is a benign brain tumor of mixed neuronal and glial origin. Tuberous sclerosis is caused by loss-of-function mutations in one of two genes, TSC1 or TSC2. The normal cellular proteins encoded by these genes, hamartin and tuberin, respectively, form a heterodimer that suppresses cell growth in the central nervous system by dampening the phosphatidylinositol 3–kinase signal transduction pathway. The authors review the clinical and neuropathological features of TS as well as recent research into the molecular biology of this disease. Through this work, investigators are beginning to resolve the paradoxical findings that malignant cancers seldom arise in patients with TS, even though the signaling molecules involved are key mediators of cancer cell growth.

Download Full-text

Mosaicism in Tuberous Sclerosis Complex: A Case Report, Literature Review, and Original Data from Danish Hospitals

EMJ Dermatology ◽

10.33590/emjdermatol/21-00082 ◽

2021 ◽

pp. 98-105

Author(s):

Julie Loft Nagel ◽

Maja Patricia Smerdel ◽

Lisbeth Birk Møller ◽

Lotte Andreasen ◽

Anette Bygum

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Original Data ◽

Hereditary Disease ◽

Loss Of Function ◽

Low Level ◽

Multiple Organs ◽

Organ Systems

Tuberous sclerosis complex (TSC) is an autosomal dominant hereditary disease with hamartomatous growths in multiple organs due to loss-of-function variants in TSC1 or TSC2. In approximately 15% of patients with clinical TSC, no pathogenic variant can be identified, and low-level mosaicism is suggested to be one of the reasons. Mosaicism is well-known in TSC and challenges the molecular genetic diagnosis. The advent of next-generation sequencing has improved the diagnostics in TSC including in patients with mosaicism. The TSC phenotype varies widely, and mosaic patients with TSC are often considered to have a milder phenotype. Here, the authors describe a patient with mosaic TSC with a 10% variant allele fraction and manifestations in three organ systems (skin, eyes, and kidneys). Furthermore, the authors studied existing literature about phenotypic organ manifestations in patients with mosaic TSC. No clear definition of the phenotype of patients with mosaic TSC could be established, but unilateral angiofibromas and the absence of tubers and a subependymal nodule could indicate mosaicism. The case shows that patients with low-level mosaic TSC can have multiple affected organ systems though still a mild clinical picture.

Download Full-text

Retracted Tuberous sclerosis complex: molecular pathogenesis and animal models

Neurosurgical FOCUS ◽

10.3171/foc.2006.20.1.5 ◽

2006 ◽

Vol 20 (1) ◽

pp. 1-6 ◽

Cited By ~ 8

Author(s):

Leandro R. Piedimonte ◽

Ian K. Wailes ◽

Howard L. Weiner

Keyword(s):

Animal Models ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Conditional Knockout ◽

Signaling Complex ◽

Normal Functions ◽

Similar Disease ◽

The Central Nervous System ◽

Cortical Tubers ◽

The Brain

Mutations in one of two genes, TSC1 and TSC2, result in a similar disease phenotype by disrupting the normal interaction of their protein products, hamartin and tuberin, which form a functional signaling complex. Disruption of these genes in the brain results in abnormal cellular differentiation, migration, and proliferation, giving rise to the characteristic brain lesions of tuberous sclerosis complex (TSC) called cortical tubers. The most devastating complications of TSC affect the central nervous system and include epilepsy, mental retardation, autism, and glial tumors. Relevant animal models, including conventional and conditional knockout mice, are valuable tools for studying the normal functions of tuberin and hamartin and the way in which disruption of their expression gives rise to the variety of clinical features that characterize TSC. In the future, these animals will be invaluable preclinical models for the development of highly specific and efficacious treatments for children affected with TSC.

Download Full-text

Balancing biosynthesis and bioenergetics: metabolic programs in oncogenesis

Endocrine Related Cancer ◽

10.1677/erc-10-0106 ◽

2010 ◽

Vol 17 (4) ◽

pp. R287-R304 ◽

Cited By ~ 40

Author(s):

Jennifer F Barger ◽

David R Plas

Keyword(s):

Cell Growth ◽

Cancer Cell ◽

Cell Metabolism ◽

Signal Transduction Pathway ◽

Building Blocks ◽

Cancer Cell Growth ◽

Growth And Survival ◽

Pathway Activation ◽

Cancer Cell Metabolism ◽

Programed Cell Death

Cancer biologists' search for new chemotherapy targets is reinvigorating the study of how cancer cell metabolism determines both oncogenic potential and chemotherapeutic responses. Oncogenic metabolic programs support the bioenergetics associated with resistance to programed cell death and provide biosynthetic building blocks for cell growth and mitogenesis. Both signal transduction pathway activation and direct mutations in key metabolic enzymes can activate the metabolic programs that support cancer cell growth. Cancer-associated metabolic programs include glycolysis, glutamine oxidation, and fatty acid metabolism. Recent observations are revealing the regulatory mechanisms that activate cancer-associated metabolism, and the competitive advantages provided to transformed cells by their metabolic programs. In this study, we review recent results illustrating the mechanisms and functional impact of each of these oncogenic metabolic programs in cancer cell growth and survival.

Download Full-text

Loss‐of‐function genetic screening identifies ALDOA as an essential driver for liver cancer cell growth under hypoxia

Hepatology ◽

10.1002/hep.31846 ◽

2021 ◽

Author(s):

Yi Niu ◽

Ziyou Lin ◽

Arabella Wan ◽

Lei Sun ◽

Shijia Yan ◽

...

Keyword(s):

Cell Growth ◽

Liver Cancer ◽

Cancer Cell ◽

Genetic Screening ◽

Liver Cancer Cell ◽

Loss Of Function ◽

Cancer Cell Growth

Download Full-text

Tuberous sclerosis complex

Anais Brasileiros de Dermatologia ◽

10.1590/s0365-05962012000200001 ◽

2012 ◽

Vol 87 (2) ◽

pp. 184-196 ◽

Cited By ~ 11

Author(s):

Daniela Araujo Rodrigues ◽

Ciro Martins Gomes ◽

Izelda Maria Carvalho Costa

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Autosomal Dominant ◽

Multisystem Disorder ◽

Therapeutic Trials ◽

Multiple Organs ◽

Tissue Replacement ◽

History Of ◽

Neurocutaneous Syndrome ◽

Made In

Tuberous Sclerosis Complex, also known as Epiloia or Bourneville-Pringle disease is an autosomal dominant neurocutaneous syndrome with variable clinical expression. It is a multisystem disorder that may be associated with hamartomas in multiple organs in an unpredictable manner. The dermatologist plays an essential role in the history of the disease, since skin manifestations represent the most prevalent clinical features, enabling early diagnosis and intervention in its natural course. This article aims to inform the scientific community about advances made in the study of genetics and molecular biology. Recent findings regarding stimulation of tumor growth have been changing the history of this condition, making therapeutic trials with topical and systemic drugs possible. Knowledge of these topics enables better management of the patients affected, since tissue replacement by tumors can result in significant morbidity and mortality.

Download Full-text

Aspects of tuberous sclerosis complex (TSC) protein function in the brain

Biochemical Society Transactions ◽

10.1042/bst0310579 ◽

2003 ◽

Vol 31 (3) ◽

pp. 579-583 ◽

Cited By ~ 15

Author(s):

V. Ramesh

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Protein Function ◽

Direct Interaction ◽

Wild Type ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Dominant Disease ◽

The Central Nervous System ◽

Cortical Tubers

Tuberous sclerosis complex (TSC), an autosomal dominant disease caused by mutations in either TSC1 or TSC2, is characterized by the development of hamartomas in a variety of organs. Concordant with the tumour-suppressor model, loss of heterozygosity (LOH) is known to occur in these hamartomas at both TSC1 and TSC2 loci. LOH has been documented in renal angiomyolipomas, but loss of the wild-type allele in cortical tubers appears very uncommon. We analysed 24 hamartomas from 10 patients for second-hit mutations by several methods, and found no evidence for the inactivation of the second allele in many of the central nervous system (CNS) lesions, including tumours that appear to be clonally derived. We believe that somatic mutations in TSC1 and TSC2 resulting in the loss of wild-type alleles may not be necessary in some tumour types, and other mechanisms may contribute to tumorigenesis in this setting. We have shown that hamartin interacts with neurofilament light chain (NF-L) and could integrate the neuronal cytoskeleton through its direct interaction with NF-L and ERM (ezrin/radixin/moeisin) proteins. Our unpublished work further documents the binding of tuberin with Pam, a protein associated with c-Myc, which is enriched in brain. All these observations suggest that the tuberin–hamartin complex is likely to have distinct functions in the CNS.

Download Full-text

TUBEROUS SCLEROSIS : ITS VARIED PRESENTATION

10.36106/paripex/1901465 ◽

2020 ◽

pp. 1-2

Author(s):

Puja D. Nandaniya

Keyword(s):

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Autosomal Dominant ◽

Benign Tumors ◽

Gingival Hyperplasia ◽

Oral Manifestations ◽

Enamel Hypoplasia ◽

Multiple Organs ◽

Neurocutaneous Syndrome ◽

The Brain

Tuberous sclerosis complex is an unusual autosomal dominant neurocutaneous syndrome characterized by the development of benign tumors affecting different body systems affecting the brain, skin, retina, and viscera. It is characterized by cutaneous changes, neurologic conditions, and the formation of hamartomas in multiple organs leading to morbidity and mortality. The most common oral manifestations are fibromas, gingival hyperplasia, and enamel hypoplasia. The management of these patients is often multidisciplinary involving specialists from various fields. Here, we present a case report of a 26-old-year male patient with characteristic clinical, radiological, and histological features of tuberous sclerosis complex.

Download Full-text

A Young Girl with Tuberous Sclerosis Presenting with Recurrent Episodes of Convulsion & Right Sided Hemiparesis

Journal of Medicine ◽

10.3329/jom.v17i2.30080 ◽

2016 ◽

Vol 17 (2) ◽

pp. 125-129

Author(s):

Partha Sarathi Sarker ◽

Sarmin Akhter ◽

Md Saidur Rahman ◽

Md Monjurul Kader Chowdhury ◽

Palash Kumar Biswas ◽

...

Keyword(s):

Mental Retardation ◽

Tuberous Sclerosis ◽

Tuberous Sclerosis Complex ◽

Skin Lesions ◽

Young Girl ◽

Neurocutaneous Syndrome ◽

Cortical Tubers ◽

Minor Criteria ◽

Progressive Weakness ◽

Subependymal Nodules

Tuberous Sclerosis Complex (TSC) is a neurocutaneous syndrome manifested by involvement of multiple system including CNS, kidney, skin, heart, lungs & eye. It is usually characterized by triad of skin lesions (96%), seizures (90%) & mental retardation (70%). Most common lesions associated with TSC are angiofibroma of face, ashleaf macules, shagreen patches, subependymal nodules, cortical tubers, mental retardation &angiomyolipoma of kidney. Here we report a case of a 14 years old girl who presented with recurrent episodes of convulsion, mental retardation & progressive weakness of right side of body. We investigated the patient to find out the etiology of her illness. After cranial imaging & other necessary investigations several major & minor criteria were established, which helped us to reach the final diagnosisJ MEDICINE July 2016; 17 (2) : 125-129

Download Full-text