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American Journal of Human Genetics Jun 2023Tuberous sclerosis complex (TSC) is a neurogenetic disorder due to loss-of-function TSC1 or TSC2 variants, characterized by tumors affecting multiple organs, including...
Tuberous sclerosis complex (TSC) is a neurogenetic disorder due to loss-of-function TSC1 or TSC2 variants, characterized by tumors affecting multiple organs, including skin, brain, heart, lung, and kidney. Mosaicism for TSC1 or TSC2 variants occurs in 10%-15% of individuals diagnosed with TSC. Here, we report comprehensive characterization of TSC mosaicism by using massively parallel sequencing (MPS) of 330 TSC samples from a variety of tissues and fluids from a cohort of 95 individuals with mosaic TSC. TSC1 variants in individuals with mosaic TSC are much less common (9%) than in germline TSC overall (26%) (p < 0.0001). The mosaic variant allele frequency (VAF) is significantly higher in TSC1 than in TSC2, in both blood and saliva (median VAF: TSC1, 4.91%; TSC2, 1.93%; p = 0.036) and facial angiofibromas (median VAF: TSC1, 7.7%; TSC2 3.7%; p = 0.004), while the number of TSC clinical features in individuals with TSC1 and TSC2 mosaicism was similar. The distribution of mosaic variants across TSC1 and TSC2 is similar to that for pathogenic germline variants in general TSC. The systemic mosaic variant was not present in blood in 14 of 76 (18%) individuals with TSC, highlighting the value of analysis of multiple samples from each individual. A detailed comparison revealed that nearly all TSC clinical features are less common in individuals with mosaic versus germline TSC. A large number of previously unreported TSC1 and TSC2 variants, including intronic and large rearrangements (n = 11), were also identified.
Topics: Humans; Tumor Suppressor Proteins; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Mutation; Tuberous Sclerosis Complex 1 Protein; Phenotype
PubMed: 37141891
DOI: 10.1016/j.ajhg.2023.04.002 -
Ideggyogyaszati Szemle Mar 2017Tuberous sclerosis complex (TSC) is an autosomal dominant disease due to the uncontrolled differentiation, proliferation, and migration of cells in several organs.... (Review)
Review
Tuberous sclerosis complex (TSC) is an autosomal dominant disease due to the uncontrolled differentiation, proliferation, and migration of cells in several organs. Clinical expression is highly variable, from mild skin findings and asymptomatic brain lesions to seizures, mental retardation, autism, and potentially fatal kidney, cardiac, or pulmonary disease. Aim of this paper is to summarize the diagnostic criteria, surveillance and therapeutic issues of this multisystemic disorder emphasizing the most important neurological consequences. Presenting the state-of-the-art management recommendations and comparing them with the local protocols, we hope that our review might help in the proper assessment of one of the most important single gene disorder.
Topics: Female; Humans; Male; Tuberous Sclerosis
PubMed: 29870614
DOI: 10.18071/isz.70.0097 -
Dermatology Online Journal Jan 2007A 46-year-old woman presented with multiple, skin-colored, hyperpigmented, dome-shaped facial papules. Histopathologic examination was consistent with angiofibromas....
A 46-year-old woman presented with multiple, skin-colored, hyperpigmented, dome-shaped facial papules. Histopathologic examination was consistent with angiofibromas. Clinical history and examination were consistent with tuberous sclerosis. The clinical manifestations, pathogenesis, evaluation, and treatment of tuberous sclerosis are discussed.
Topics: Biopsy; Diagnosis, Differential; Female; Frontal Bone; Genetic Predisposition to Disease; Humans; Lacrimal Apparatus; Middle Aged; Skin; Tomography, X-Ray Computed; Tuberous Sclerosis
PubMed: 17511955
DOI: No ID Found -
Archives of Disease in Childhood Sep 2017Tuberous sclerosis complex (TSC) is a multisystem genetic disorder stemming from unregulated activation of the mammalian target of rapamycin (mTOR) pathway, resulting in... (Review)
Review
Tuberous sclerosis complex (TSC) is a multisystem genetic disorder stemming from unregulated activation of the mammalian target of rapamycin (mTOR) pathway, resulting in the growth of hamartomas in multiple organs. TSC-related skin lesions often develop early in life and can be disfiguring, emotionally distressful and even painful at times. Recognition of TSC-associated skin features by paediatricians can be a catalyst for facilitating early implementation of treatment strategies and establishing appropriate follow-up care. The range of potential treatment options for symptomatic or disfiguring TSC-associated skin lesions includes non-pharmacological (surgical excision, laser therapy) and pharmacological (eg, topical or systemic mTOR inhibitors) alternatives. In this review, we discuss the relevance of TSC-associated skin findings, highlight available treatment options, review guideline recommendations and emphasise the role of the primary care physician in the management of this complex disease.
Topics: Antibiotics, Antineoplastic; Humans; Pediatricians; Physician's Role; Practice Guidelines as Topic; Sirolimus; Skin Diseases; Skin Neoplasms; TOR Serine-Threonine Kinases; Tuberous Sclerosis
PubMed: 28351834
DOI: 10.1136/archdischild-2016-312001 -
International Journal of Molecular... Jun 2021The mammalian target of the rapamycin (mTOR) system plays multiple, important roles in the brain, regulating both morphology, such as cellular size, shape, and position,... (Review)
Review
The mammalian target of the rapamycin (mTOR) system plays multiple, important roles in the brain, regulating both morphology, such as cellular size, shape, and position, and function, such as learning, memory, and social interaction. Tuberous sclerosis complex (TSC) is a congenital disorder caused by a defective suppressor of the mTOR system, the TSC1/TSC2 complex. Almost all brain symptoms of TSC are manifestations of an excessive activity of the mTOR system. Many children with TSC are afflicted by intractable epilepsy, intellectual disability, and/or autism. In the brains of infants with TSC, a vicious cycle of epileptic encephalopathy is formed by mTOR hyperactivity, abnormal synaptic structure/function, and excessive epileptic discharges, further worsening epilepsy and intellectual/behavioral disorders. Molecular target therapy with mTOR inhibitors has recently been proved to be efficacious for epilepsy in human TSC patients, and for autism in TSC model mice, indicating the possibility for pharmacological treatment of developmental synaptic disorders.
Topics: Animals; Brain; Disease Management; Disease Models, Animal; Disease Susceptibility; Epilepsy; Genetic Predisposition to Disease; Humans; Symptom Assessment; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein
PubMed: 34206526
DOI: 10.3390/ijms22136677 -
BMC Medicine Aug 2023Tuberous sclerosis complex (TSC) is a rare and complex genetic disorder, associated with tumor growth in various organ systems, epilepsy, and a range of neuropsychiatric...
BACKGROUND
Tuberous sclerosis complex (TSC) is a rare and complex genetic disorder, associated with tumor growth in various organ systems, epilepsy, and a range of neuropsychiatric manifestations including intellectual disability. With improving patient-centered care and targeted therapies, patient-reported outcome measures (PROMs) are needed to measure the impact of TSC manifestations on daily functioning. The aim of this study was to develop a TSC-specific PROM for adults that captures the impact of TSC on physical functions, mental functions, activity and participation, and the social support individuals with TSC receive, called the TSC-PROM.
METHODS
COSMIN methodology was used to develop a self-reported and proxy-reported version. Development and validation consisted of the following studies: PROM development, content validity, structural validity, internal consistency, and construct validity. The International Classification of Functioning and Disability was used as a framework. Content validity was examined by a multidisciplinary expert group and cognitive interview study. Structural and construct validity, and internal consistency were examined in a large cohort, using confirmatory factor analysis, hypotheses testing, and Cronbach's alpha.
RESULTS
The study resulted in an 82-item self version and 75-item proxy version of the TSC-PROM with four subscales (physical functions 18 and 19 items, mental functions 37 and 28 items, activities and participation 13 and 14 items, social support 13 items, for self version and proxy version respectively). Sufficient results were found for structural validity with sufficient unidimensionality for each subscale. With regard to construct validity, 82% of the hypotheses were met for the self version and 59% for the proxy version. The PROM showed good internal consistency (Cronbach's alpha 0.78-0.97).
CONCLUSIONS
We developed a PROM for adults with TSC, named TSC-PROM, showing sufficient evidence for reliability and validity that can be used in clinical and research settings to systematically gain insight into their experiences. It is the first PROM in TSC that addresses the impact of specific TSC manifestations on functioning, providing a valuable, patient-centered addition to the current clinical outcomes.
Topics: Adult; Humans; Surveys and Questionnaires; Tuberous Sclerosis; Reproducibility of Results; Self Report; Patient Reported Outcome Measures; Quality of Life
PubMed: 37553648
DOI: 10.1186/s12916-023-03012-4 -
Annals of the New York Academy of... Jan 2010Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results from mutations in the TSC1 or TSC2 genes and is associated with hamartoma formation in... (Review)
Review
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results from mutations in the TSC1 or TSC2 genes and is associated with hamartoma formation in multiple organ systems. The neurological manifestations of TSC are particularly challenging and include infantile spasms, intractable epilepsy, cognitive disabilities, and autism. Progress over the past 15 years has demonstrated that the TSC1 or TSC2 encoded proteins modulate cell function via the mTOR signaling cascade and serve as keystones in regulating cell growth and proliferation. The mTOR pathway provides an intersection for an intricate network of protein cascades that respond to cellular nutrition, energy levels, and growth-factor stimulation. In the brain, TSC1 and TSC2 have been implicated in cell body size, dendritic arborization, axonal outgrowth and targeting, neuronal migration, cortical lamination, and spine formation. Antagonism of the mTOR pathway with rapamycin and related compounds may provide new therapeutic options for TSC patients.
Topics: Animals; Axons; Cell Division; Cerebral Cortex; Dendrites; Drosophila; Drosophila Proteins; Hamartoma; Humans; Infant; Intracellular Signaling Peptides and Proteins; Nervous System Diseases; Phosphorylation; Protein Serine-Threonine Kinases; Spine; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins
PubMed: 20146692
DOI: 10.1111/j.1749-6632.2009.05117.x -
International Journal of Molecular... Mar 2023Over the years, several studies have shown that kinase-regulated signaling pathways are involved in the development of rare genetic diseases. The study of the mechanisms... (Review)
Review
Over the years, several studies have shown that kinase-regulated signaling pathways are involved in the development of rare genetic diseases. The study of the mechanisms underlying the onset of these diseases has opened a possible way for the development of targeted therapies using particular kinase inhibitors. Some of these are currently used to treat other diseases, such as cancer. This review aims to describe the possibilities of using kinase inhibitors in genetic pathologies such as tuberous sclerosis, RASopathies, and ciliopathies, describing the various pathways involved and the possible targets already identified or currently under study.
Topics: Humans; TOR Serine-Threonine Kinases; Signal Transduction; Tuberous Sclerosis
PubMed: 36982349
DOI: 10.3390/ijms24065276 -
Pharmacological Research Sep 2023Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterised by abnormal cell proliferation and differentiation that affects multiple organs and can... (Review)
Review
Tuberous sclerosis complex (TSC) 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.
Topics: Humans; Everolimus; Tuberous Sclerosis; Sirolimus; Mechanistic Target of Rapamycin Complex 1
PubMed: 37549757
DOI: 10.1016/j.phrs.2023.106884 -
Tidsskrift For Den Norske Laegeforening... Mar 2007
Topics: Clinical Competence; Humans; Patient Care Team; Tuberous Sclerosis
PubMed: 17435801
DOI: No ID Found