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Genes Mar 2024The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival. Upregulation of the mTOR pathway has been... (Review)
Review
The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival. Upregulation of the mTOR pathway has been shown to cause malformations of cortical development, medically refractory epilepsies, and neurodevelopmental disorders, collectively described as mTORopathies. Tuberous sclerosis complex (TSC) serves as the prototypical mTORopathy. Characterized by the development of benign tumors in multiple organs, pathogenic variants in or disrupt the TSC protein complex, a negative regulator of the mTOR pathway. Variants in critical domains of the TSC complex, especially in the catalytic TSC2 subunit, correlate with increased disease severity. Variants in less crucial exons and non-coding regions, as well as those undetectable with conventional testing, may lead to milder phenotypes. Despite the assumption of complete penetrance, expressivity varies within families, and certain variants delay disease onset with milder neurological effects. Understanding these genotype-phenotype correlations is crucial for effective clinical management. Notably, 15% of patients have no mutation identified by conventional genetic testing, with the majority of cases postulated to be caused by somatic variants which present complex diagnostic challenges. Advancements in genetic testing, prenatal screening, and precision medicine hold promise for changing the diagnostic and treatment paradigm for TSC and related mTORopathies. Herein, we explore the genetic and molecular mechanisms of TSC and other mTORopathies, emphasizing contemporary genetic methods in understanding and diagnosing the condition.
Topics: Humans; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Mutation; Genetic Testing; TOR Serine-Threonine Kinases
PubMed: 38540392
DOI: 10.3390/genes15030332 -
BMC Pediatrics Jun 2023To investigate the complete clinical spectrum of individuals with paediatric tuberous sclerosis complex in southern Sweden and explore changes over time. (Observational Study)
Observational Study
AIM
To investigate the complete clinical spectrum of individuals with paediatric tuberous sclerosis complex in southern Sweden and explore changes over time.
METHODS
In this retrospective observational study, 52 individuals aged up to 18 years at the study start were followed-up at regional hospitals and centres for habilitation from 2000 to 2020.
RESULTS
Cardiac rhabdomyoma was detected prenatally/neonatally in 69.2% of the subjects born during the latest ten years of the study period. Epilepsy was diagnosed in 82.7% of subjects, and 10 (19%) were treated with everolimus, mainly (80%) for a neurological indication. Renal cysts were detected in 53%, angiomyolipomas in 47%, astrocytic hamartomas in 28% of the individuals. There was a paucity of standardized follow-up of cardiac, renal, and ophthalmological manifestations and no structured transition to adult care.
CONCLUSION
Our in-depth analysis shows a clear shift towards an earlier diagnosis of tuberous sclerosis complex in the latter part of the study period, where more than 60% of cases showed evidence of this condition already in utero due to the presence of a cardiac rhabdomyoma. This allows for preventive treatment of epilepsy with vigabatrin and early intervention with everolimus for potential mitigation of other symptoms of tuberous sclerosis complex.
Topics: Adult; Child; Humans; Aged; Tuberous Sclerosis; Everolimus; Rhabdomyoma; Sweden; Early Intervention, Educational; Heart Neoplasms
PubMed: 37386496
DOI: 10.1186/s12887-023-04137-4 -
Cold Spring Harbor Molecular Case... Apr 2022Tuberous sclerosis complex (TSC) is an inheritable disorder characterized by the formation of benign yet disorganized tumors in multiple organ systems. Germline...
Tuberous sclerosis complex (TSC) is an inheritable disorder characterized by the formation of benign yet disorganized tumors in multiple organ systems. Germline mutations in the (hamartin) or more frequently (tuberin) genes are causative for TSC. The malignant manifestations of TSC, pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML), may also occur as independent sporadic perivascular epithelial cell tumor (PEComa) characterized by somatic mutations. Thus, discerning TSC from the copresentation of sporadic LAM and sporadic AML may be obscured in TSC patients lacking additional features. In this report, we present a case study on a single patient initially reported to have sporadic LAM and a mucinous duodenal adenocarcinoma deficient in DNA mismatch repair proteins. Moreover, the patient had a history of Wilms' tumor, which was reclassified as AML following the LAM diagnosis. Therefore, we investigated the origins and relatedness of these tumors. Using germline whole-genome sequencing, we identified a premature truncation in one of the patient's alleles. Using immunohistochemistry, loss of tuberin expression was observed in AML and LAM tissue. However, no evidence of a somatic loss of heterozygosity or DNA methylation epimutations was observed at the locus, suggesting alternate mechanisms may contribute to loss of the tumor suppressor protein. In the mucinous duodenal adenocarcinoma, no causative mutations were found in the DNA mismatch repair genes , or Rather, clonal deconvolution analyses were used to identify mutations contributing to pathogenesis. This report highlights both the utility of using multiple sequencing techniques and the complexity of interpreting the data in a clinical context.
Topics: Adenocarcinoma; Angiomyolipoma; Female; Humans; Kidney Neoplasms; Leukemia, Myeloid, Acute; Male; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins
PubMed: 35483879
DOI: 10.1101/mcs.a006182 -
Medicina Aug 2022Tuberous sclerosis complex is an autosomal dominant genetic multisystemic disorder caused primarily by mutations in one of the two tumor suppressor genes TSC1 or TSC2,...
Tuberous sclerosis complex is an autosomal dominant genetic multisystemic disorder caused primarily by mutations in one of the two tumor suppressor genes TSC1 or TSC2, resulting in increased activation of the mTOR pathway. Regarding clinical manifestations, a wide range of phenotypic variability exists, with symptoms constellations that may differ in affected organs (brain, skin, heart, eyes, kidneys, lungs), age of presentation and severity, but usually with great impact in biopsychosocial aspects of health and in quality of life. Main clinical neurological features are epilepsy (frequently, antiepileptic drug-resistant epilepsy), neuropsychiatric disorders, and subependymal giant cell astrocytomas. Recently, many therapeutic strategies have developed, including preventive treatment of epilepsy, new options for treatment of epilepsy as cannabidiol, mTOR inhibitors, ketogenic diet, and a more precise epilepsy surgery. Subependymal giant cell astrocytomas may require surgical procedures or mTOR inhibitors treatment. mTOR inhibitors may also be useful for other comorbidities. To improve quality of life of patients with tuberous sclerosis complex, it is essential to be able to deliver an integrated approach by specialized multidisciplinary teams, coordinated with primary care physicians and health professionals, that include access to treatments, attention of psychosocial aspects, and an adequate health care transition from pediatric to adult care.
Topics: Adult; Astrocytoma; Child; Epilepsy; Humans; Quality of Life; Transition to Adult Care; Tuberous Sclerosis
PubMed: 36054862
DOI: No ID Found -
Pediatric Neurology Jul 2016On March 10 to March 12, 2015, the National Institute of Neurological Disorders and Stroke and the Tuberous Sclerosis Alliance sponsored a workshop in Bethesda,...
On March 10 to March 12, 2015, the National Institute of Neurological Disorders and Stroke and the Tuberous Sclerosis Alliance sponsored a workshop in Bethesda, Maryland, to assess progress and new opportunities for research in tuberous sclerosis complex with the goal of updating the 2003 Research Plan for Tuberous Sclerosis (http://www.ninds.nih.gov/about_ninds/plans/tscler_research_plan.htm). In addition to the National Institute of Neurological Disorders and Stroke and Tuberous Sclerosis Alliance, participants in the strategic planning effort and workshop included representatives from six other Institutes of the National Institutes of Health, the Department of Defense Tuberous Sclerosis Complex Research Program, and a broad cross-section of basic scientists and clinicians with expertise in tuberous sclerosis complex along with representatives from the pharmaceutical industry. Here we summarize the outcomes from the extensive premeeting deliberations and final workshop recommendations, including (1) progress in the field since publication of the initial 2003 research plan for tuberous sclerosis complex, (2) the key gaps, needs, and challenges that hinder progress in tuberous sclerosis complex research, and (3) a new set of research priorities along with specific recommendations for addressing the major challenges in each priority area. The new research plan is organized around both short-term and long-term goals with the expectation that progress toward specific objectives can be achieved within a five to ten year time frame.
Topics: Animals; Biomedical Research; Disease Models, Animal; Goals; Humans; Strategic Planning; Tuberous Sclerosis; United States
PubMed: 27267556
DOI: 10.1016/j.pediatrneurol.2016.03.015 -
Journal of Child Neurology Dec 2015Approximately 50% of patients with the genetic disease tuberous sclerosis complex present with autism spectrum disorder. Although a number of studies have investigated... (Review)
Review
Approximately 50% of patients with the genetic disease tuberous sclerosis complex present with autism spectrum disorder. Although a number of studies have investigated the link between autism and tuberous sclerosis complex, the etiology of autism spectrum disorder in these patients remains unclear. Abnormal cerebellar function during critical phases of development could disrupt functional processes in the brain, leading to development of autistic features. Accordingly, the authors review the potential role of cerebellar dysfunction in the pathogenesis of autism spectrum disorder in tuberous sclerosis complex. The authors also introduce conditional knockout mouse models of Tsc1 and Tsc2 that link cerebellar circuitry to the development of autistic-like features. Taken together, these preclinical and clinical investigations indicate the cerebellum has a profound regulatory role during development of social communication and repetitive behaviors.
Topics: Animals; Autism Spectrum Disorder; Cerebellum; TOR Serine-Threonine Kinases; Tuberous Sclerosis
PubMed: 26303409
DOI: 10.1177/0883073815600870 -
The New England Journal of Medicine May 2017
Topics: Aged; Angiofibroma; Face; Humans; Male; Nails; Renal Insufficiency, Chronic; Skin Neoplasms; Tuberous Sclerosis
PubMed: 28514607
DOI: 10.1056/NEJMicm1610501 -
Italian Journal of Pediatrics Sep 2023Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with different initial symptoms and complex clinical manifestations. A 14-year-old female patient... (Review)
Review
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with different initial symptoms and complex clinical manifestations. A 14-year-old female patient presented with persistent fever and severe headache. Medical imaging examinations revealed multiple abnormal intracranial lesions. The patient had previously been misdiagnosed with "encephalitis and acute disseminated encephalomyelitis" after visiting numerous hospitals. Eventually, by combing the characteristics of the case and genetic testing results, the patient was diagnosed with TSC accompanied by Mycoplasma pneumoniae infection. The purpose of this case report and literature review is to improve understanding of the clinical diagnosis and treatment of TSC so as to avoid misdiagnosis, missed diagnosis, and overtreatment.
Topics: Female; Humans; Adolescent; Tuberous Sclerosis; Encephalitis; Hospitals; Physical Examination; Pneumonia, Mycoplasma
PubMed: 37679848
DOI: 10.1186/s13052-023-01490-z -
Nephron. Experimental Nephrology 2011Although not as common as other genetic renal diseases such as autosomal dominant polycystic kidney disease, patients with tuberous sclerosis complex frequently have... (Review)
Review
Although not as common as other genetic renal diseases such as autosomal dominant polycystic kidney disease, patients with tuberous sclerosis complex frequently have significant renal involvement. Recent revelations in the cell biology of these renal disease manifestations as well as effective therapies for tuberous sclerosis complex-related renal issues have heralded hope of improved renal survival and improved quality of life for the TSC patient. This review specifically addresses some of the major renal manifestations of this disease.
Topics: Angiomyolipoma; Humans; Kidney Diseases, Cystic; Kidney Neoplasms; Mutation; Nephrolithiasis; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins
PubMed: 21071977
DOI: 10.1159/000320891 -
Journal of Neurodevelopmental Disorders Feb 2022Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) is an umbrella term for the behavioural, psychiatric, intellectual, academic,... (Review)
Review
BACKGROUND
Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) is an umbrella term for the behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations of TSC. Although TAND affects 90% of individuals with TSC during their lifetime, these manifestations are relatively under-assessed, under-treated and under-researched. We performed a comprehensive scoping review of all TAND research to date (a) to describe the existing TAND research landscape and (b) to identify knowledge gaps to guide future TAND research.
METHODS
The study was conducted in accordance with stages outlined within the Arksey and O'Malley scoping review framework. Ten research questions relating to study characteristics, research design and research content of TAND levels and clusters were examined.
RESULTS
Of the 2841 returned searches, 230 articles published between 1987 and 2020 were included (animal studies = 30, case studies = 47, cohort studies = 153), with more than half published since the term TAND was coined in 2012 (118/230; 51%). Cohort studies largely involved children and/or adolescents (63%) as opposed to older adults (16%). Studies were represented across 341 individual research sites from 45 countries, the majority from the USA (89/341; 26%) and the UK (50/341; 15%). Only 48 research sites (14%) were within low-middle income countries (LMICs). Animal studies and case studies were of relatively high/high quality, but cohort studies showed significant variability. Of the 153 cohort studies, only 16 (10%) included interventions. None of these were non-pharmacological, and only 13 employed remote methodologies (e.g. telephone interviews, online surveys). Of all TAND clusters, the autism spectrum disorder-like cluster was the most widely researched (138/230; 60%) and the scholastic cluster the least (53/200; 27%).
CONCLUSIONS
Despite the recent increase in TAND research, studies that represent participants across the lifespan, LMIC research sites and non-pharmacological interventions were identified as future priorities. The quality of cohort studies requires improvement, to which the use of standardised direct behavioural assessments may contribute. In human studies, the academic level in particular warrants further investigation. Remote technologies could help to address many of the TAND knowledge gaps identified.
Topics: Adolescent; Aged; Autism Spectrum Disorder; Cohort Studies; Humans; Tuberous Sclerosis
PubMed: 35151277
DOI: 10.1186/s11689-022-09423-3