bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2021‒12‒19
thirteen papers selected by
Marti Cadena Sandoval
metabolic-signalling.eu
  1. Giant periungual and subungual fibromas (Koenen's tumor) of tuberous sclerosis complex.
  2. Increased expression of complement components in tuberous sclerosis complex and focal cortical dysplasia type 2B brain lesions.
  3. Early Vascular Aging in Children With Tuberous Sclerosis Complex.
  4. p38 regulates the tumor suppressor PDCD4 via the TSC-mTORC1 pathway.
  5. Leiomyomatosis-like lymphangioleiomyomatosis: A case report of the colonic manifestation of tuberous sclerosis.
  6. TiMEG: an integrative statistical method for partially missing multi-omics data.
  7. Symptom rates and profile clustering in tuberous sclerosis complex-associated neuropsychiatric disorders (TAND).
  8. Atypical unilateral exudative retinal detachment in a child affected by tuberous sclerosis.
  9. Low-Dose Everolimus Maintenance Therapy for Renal Angiomyolipoma Associated With Tuberous Sclerosis Complex.
  10. Sleep disorders and neuropsychiatric disorders in a pediatric sample of tuberous sclerosis complex: a questionnaire-based study.
  11. Myocardial fatty foci: not all echogenic myocardial lesions in Tuberous sclerosis are rhabdomyomas.
  12. Benign Renal Tumors in Pediatric Age Group: Retrospective Analysis.
  13. Roles of mTOR in thoracic aortopathy understood by complex intracellular signaling interactions.
  1. Indian J Dermatol Venereol Leprol. 2021 May 08. pii: 10.25259/IJDVL_1194_20. [Epub ahead of print] 1-2
    Giant periungual and subungual fibromas (Koenen's tumor) of tuberous sclerosis complex.
    Indukooru Subrayalu Reddy, Vijay Kumar Somani.
      
    DOI:  https://doi.org/10.25259/IJDVL_1194_20
  2. Epilepsia. 2021 Dec 14.
    Increased expression of complement components in tuberous sclerosis complex and focal cortical dysplasia type 2B brain lesions.
    Victoria-Elisabeth Gruber, Mark J Luinenburg, Katrin Colleselli, Verena Endmayr, Jasper J Anink, Till S Zimmer, Floor Jansen, Peter Gosselaar, Roland Coras, Theresa Scholl, Ingmar Blumcke, José Pimentel, Johannes A Hainfellner, Romana Höftberger, Karl Rössler, Martha Feucht, Jackelien van Scheppingen, Eleonora Aronica, Angelika Mühlebner.
      OBJECTIVE: Increasing evidence supports the contribution of inflammatory mechanisms to the neurological manifestations of epileptogenic developmental pathologies linked to mammalian target of rapamycin (mTOR) pathway dysregulation (mTORopathies), such as tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD). In this study, we aimed to investigate the expression pattern and cellular distribution of the complement factors C1q and C3 in resected cortical tissue of clinically well-characterized patients with TSC and FCD2B.METHODS: We applied immunohistochemistry in TSC (n = 29) and FCD2B (n = 32) samples and compared them to autopsy and biopsy controls (n = 27). Furthermore, protein expression was observed via Western blot, and for descriptive colocalization studies immunofluorescence double labeling was performed.
    RESULTS: Protein expression for C3 was significantly upregulated in TSC and FCD2B white and gray matter lesions compared to controls. Staining of the synaptic vesicle protein synaptophysin showed a remarkable increase in the white matter of both TSC and FCD2B. Furthermore, confocal imaging revealed colocalization of complement factors with astroglial, microglial, neuronal, and abnormal cells in various patterns.
    SIGNIFICANCE: Our results demonstrate that the prominent activation of the complement pathway represents a common pathological hallmark of TSC and FCD2B, suggesting that complement overactivation may play a role in these mTORopathies.
    Keywords:  complement; cortical development; epilepsy; focal cortical dysplasia; inflammation; tuberous sclerosis complex
    DOI:  https://doi.org/10.1111/epi.17139
  3. Front Pediatr. 2021 ;9 767394
    Early Vascular Aging in Children With Tuberous Sclerosis Complex.
    Piotr Skrzypczyk, Anna Maria Wabik, Michał Szyszka, Sergiusz Józwiak, Przemysław Bombiński, Aleksandra Jakimów-Kostrzewa, Michał Brzewski, Małgorzata Pańczyk-Tomaszewska.
      Objectives: Experimental data indicate that activating mutations in the mTOR (mammalian target of rapamycin) pathway may lead to abnormal arterial wall structure. Vascular anomalies like arterial stenoses are reported in pediatric patients with tuberous sclerosis complex (TSC). In addition, large renal lesions (angiomyolipoma-AML and cysts) are risk factors for arterial hypertension in adult patients with TSC. This study aimed to assess blood pressure, including central blood pressure and arterial damage (early vascular aging-EVA) in children with TSC. Materials and Methods: In a group of 33 pediatric patients with TSC (11.13 ± 4.03 years, 15 boys, 18 girls), we evaluated peripheral and central office blood pressure, 24-h ambulatory blood pressure, and arterial damage: aortic pulse wave velocity (aPWV) [m/s], [Z-score], augmentation index (AIx75HR [%]), common carotid artery intima-media thickness (cIMT) [mm], [Z-score], stiffness of common carotid artery (E-tracking), renal lesions in magnetic resonance and ultrasonography, and selected biochemical parameters. The control group consisted of 33 healthy children (11.23 ± 3.28 years, 15 boys, 18 girls). Results: In TSC group 7 (21.2%) children had arterial hypertension, 27 (81.8%) children had renal angiomyolipomas, 26 (78.8%)-renal cysts, and 4 (12.1%) patients were treated with mTOR inhibitors (2 patients with everolimus and 2 patients with sirolimus) at the moment of evaluation. Children with TSC had higher central systolic blood pressure (AoSBP) (98.63 ± 9.65 vs. 90.45 ± 6.87 [mm Hg], p < 0.001), cIMT (0.42 ± 0.05 vs. 0.39 ± 0.03 [mm], p = 0.011), cIMT Z-score (0.81 ± 1.21 vs. 0.16 ± 0.57, p = 0.007), aPWV (4.78 ± 0.81 vs. 4.25 ± 0.56 [m/s], p = 0.003) and aPWV Z-score (-0.14 ± 1.15 vs. -0.96 ± 0.87, p = 0.002) compared to healthy children, without differences in AIx75HR (8.71 ± 15.90 vs. 5.24 ± 11.12 [%], p = 0.319) and stiffness of common carotid artery. In children with TSC AoSBP correlated positively with serum cystatin C concentration (r = 0.377, p = 0.030) and with maximum diameter of renal cyst (R = 0.419, p = 0.033); mean arterial pressure (MAP) 24 h Z-score correlated with serum cystatin C concentration (R = 0.433, p = 0.013); and aPWV Z-score with daily urinary albumin loss [mg/24 h] (R = 0.412, p = 0.029). Conclusions: Children with tuberous sclerosis complex are at risk of elevated central blood pressure and early vascular aging. In children with TSC, blood pressure and arterial stiffness are related to renal involvement.
    Keywords:  arterial hypertension; arterial stiffness; central blood pressure; children; common carotid artery intima-media thickness; early vascular aging; tuberous sclerosis complex
    DOI:  https://doi.org/10.3389/fped.2021.767394
  4. Cell Stress. 2021 Dec;5(12): 176-182
    p38 regulates the tumor suppressor PDCD4 via the TSC-mTORC1 pathway.
    Clarissa Braun, Karl Katholnig, Christopher Kaltenecker, Monika Linke, Nyamdelger Sukhbaatar, Markus Hengstschläger, Thomas Weichhart.
      Programmed cell death protein 4 (PDCD4) exerts critical functions as tumor suppressor and in immune cells to regulate inflammatory processes. The phosphoinositide 3-kinase (PI3K) promotes degradation of PDCD4 via mammalian target of rapamycin complex 1 (mTORC1). However, additional pathways that may regulate PDCD4 expression are largely ill-defined. In this study, we have found that activation of the mitogen-activated protein kinase p38 promoted degradation of PDCD4 in macrophages and fibroblasts. Mechanistically, we identified a pathway from p38 and its substrate MAP kinase-activated protein kinase 2 (MK2) to the tuberous sclerosis complex (TSC) to regulate mTORC1-dependent degradation of PDCD4. Moreover, we provide evidence that TSC1 and TSC2 regulate PDCD4 expression via an additional mechanism independent of mTORC1. These novel data extend our knowledge of how PDCD4 expression is regulated by stress- and nutrient-sensing pathways.
    Keywords:  MK2; PDCD4; TSC1; TSC2; cancer; mTORC1; macrophages; p38; rapamycin
    DOI:  https://doi.org/10.15698/cst2021.12.260
  5. Medicine (Baltimore). 2021 Dec 17. 100(50): e27723
    Leiomyomatosis-like lymphangioleiomyomatosis: A case report of the colonic manifestation of tuberous sclerosis.
    Ergin Erginoz, Halit Eren Taskin, Gokce Hande Cavus, Abdullah Kagan Zengin.
      INTRODUCTION: Tuberous sclerosis complex is an inherited multisystemic disorder with manifestations in various organ systems as a result of a mutation of 1 of 2 tumor suppressor genes, tuberous sclerosis complex-1 or tuberous sclerosis complex-2. Perivascular epithelioid cell tumors have been shown to be associated with these gene mutations and include a variety of tumors such as angiomyolipomas and lymphangioleiomyomatosis.PATIENT CONCERNS: In this report, we present a case of a 28-year-old woman presenting with symptoms of severe abdominal pain and nausea with a medical history of cardiac rhabdomyoma, adenoma sebaceum, Ash leaf spots, bilateral renal angiomyolipomas, and retinal hamartoma, which are manifestations of tuberous sclerosis complex. The patient was operated twice for colonic perforations in the rectosigmoid and ileocecal regions where the pathologic examination revealed multiple tumoral lesions in both specimens.
    DIAGNOSIS: The tumor consisted of a myomatous component where the nodules were composed of spindle cells with fascicular array, and a lymphangiomatous component where epithelioid cells could be observed. Immunohistochemically, smooth muscle markers (desmin and SMA) were positive and the epithelioid component showed HMB-45 positivity. A diagnosis of leiomyomatosis-like lymphangioleiomyomatosis was established due to its morphological and immunohistochemical features, the presence of the tumor in multiple foci, and widespread lymphovascular invasion.
    INTERVENTIONS: The patient had a perforation in her bowel twice during the hospital stay and underwent Hartmann operation and ileocecal resection in 2 different surgical operations.
    OUTCOMES: After the second operation the patient developed fever and was diagnosed with SARS-CoV-2 infection. No other complication was observed during her stay and the patient's follow-up was unremarkable.
    CONCLUSION: Perivascular epithelioid cell tumors are associated with tuberous sclerosis and can rarely appear in the colon. Therefore, lymphangioleiomyomatosis should be in the differential diagnosis in a tuberous sclerosis patient presenting with a colonic tumor.
    DOI:  https://doi.org/10.1097/MD.0000000000027723
  6. Sci Rep. 2021 Dec 15. 11(1): 24077
    TiMEG: an integrative statistical method for partially missing multi-omics data.
    Sarmistha Das, Indranil Mukhopadhyay.
      Multi-omics data integration is widely used to understand the genetic architecture of disease. In multi-omics association analysis, data collected on multiple omics for the same set of individuals are immensely important for biomarker identification. But when the sample size of such data is limited, the presence of partially missing individual-level observations poses a major challenge in data integration. More often, genotype data are available for all individuals under study but gene expression and/or methylation information are missing for different subsets of those individuals. Here, we develop a statistical model TiMEG, for the identification of disease-associated biomarkers in a case-control paradigm by integrating the above-mentioned data types, especially, in presence of missing omics data. Based on a likelihood approach, TiMEG exploits the inter-relationship among multiple omics data to capture weaker signals, that remain unidentified in single-omic analysis or common imputation-based methods. Its application on a real tuberous sclerosis dataset identified functionally relevant genes in the disease pathway.
    DOI:  https://doi.org/10.1038/s41598-021-03034-z
  7. J Neurodev Disord. 2021 Dec 13. 13(1): 60
    Symptom rates and profile clustering in tuberous sclerosis complex-associated neuropsychiatric disorders (TAND).
    Samuel Alperin, Darcy A Krueger, David N Franz, Karen D Agricola, Gabrielle Stires, Paul S Horn, Jamie K Capal.
      BACKGROUND: Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric difficulties, appropriately termed TSC-Associated Neuropsychiatric Disorders (TAND). The objectives of the study were to analyze the rates of TAND symptoms in a cohort of patients seen at the TSC Center of Excellence at Cincinnati Children's Hospital and to identify clinically meaningful profiles based on TAND symptoms.METHODS: Data from the TAND Checklist was obtained from participants seen at the TSC Center of Excellence at Cincinnati Children's Hospital Medical Center from June 2015 to August 2018. Cluster and factor analyses for each TAND symptom were performed. Factor scores were then calculated for participants, and a K-means cluster analysis of these scores was used to empirically identify distinct overall TAND symptom profiles occurring in TSC.
    RESULTS: A total of 1545 checklists was completed for 668 participants (37% adults and 63% children). Approximately 90% of participants reported at least one TAND symptom with an average of 12 symptoms (out of 29). Symptom rates ranged between 5 and 60%. The most common symptoms were neuropsychologic symptoms. A seven-cluster and seven-factor solution were found to be optimal. K-means cluster analysis resulted in a seven-profile solution, ranging from low to high symptom burden.
    CONCLUSION: This study is the first to identify natural phenotypic profiles of TAND symptoms. Study of specific TAND subpopulations with shared profiles may facilitate better understanding of the underlying biology of TAND and better assessment of more targeted treatments.
    Keywords:  Intellectual disability; TSC-associated neuropsychiatric disorders (TAND); Tuberous sclerosis complex
    DOI:  https://doi.org/10.1186/s11689-021-09408-8
  8. Eur J Ophthalmol. 2020 Dec 16. 1120672120980950
    Atypical unilateral exudative retinal detachment in a child affected by tuberous sclerosis.
    Michele Coppola, Barbara Cavallotti, Martina Suzani, Alessandro Marchese, Francesco Bandello.
      INTRODUCTION: Tuberous sclerosis complex (TSC) is a rare hereditary phakomatosis. The clinical features can include benign growths in the central nervous system, tumors of various visceral organs, and retinal or optic disc astrocytic hamartomas in the nerve fiber layer. Here we present the case of a child with known TSC developing Coats-like manifestations.CASE DESCRIPTION: A 22-month-old girl with known TSC and retinal hamartoma followed since birth presented for the development of exotropia and leukocoria in the left eye. Fundus examination of the left eye showed blurred optic disc, macular star, and yellow retinal exudation in the temporal area. In addition, the left eye showed marked retinal vascular tortuosity and telangiectasias. The patient underwent brain and orbit magnetic resonance imaging, revealing heterotopic gray matter nodulations along ependyma of both lateral ventricles, with partial calcification, and a posterior flattening of the left eye.
    CONCLUSION: This report shows a rare case of Coats-like disease in a child with tuberous sclerosis. In case of presence of Coats' manifestations associated with atypical retinal or systemic findings, genetic diseases should be considered in the differential diagnosis.
    Keywords:  Retinal detachment; childhood tumors; genetic disease/congenital abnormalities; pediatric ophthalmology; phakomatoses; retina; vitreous/retinal disease
    DOI:  https://doi.org/10.1177/1120672120980950
  9. Front Med (Lausanne). 2021 ;8 744050
    Low-Dose Everolimus Maintenance Therapy for Renal Angiomyolipoma Associated With Tuberous Sclerosis Complex.
    Cong Luo, Wen-Rui Ye, Xiong-Bin Zu, Min-Feng Chen, Lin Qi, Yang-Le Li, Yi Cai.
      Objective: To assess the safety and efficacy of low-dose everolimus maintenance therapy for tuberous sclerosis complex-related renal angiomyolipoma (TSC-RAML) patients that had previously undergone standard-dose treatment for a minimum of 6 months. Materials and Methods: In total, 24 patients with a definitive TSC diagnosis were enrolled from April 2018 - April 2019 at Xiangya Hospital, Central South University. All patients underwent low-dose everolimus maintenance therapy following standard-dose everolimus induction therapy for a minimum of 6 months. Patients additionally underwent TSC1/TSC2 genetic testing, And they were followed-up at 3, 6, 12, 18, and 24 months. The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) criteria were used to monitor patient RAML responses, while adverse events (AEs) were assessed as per the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). P < 0.05 was the significance level for all analyses, which were performed using SPSS 19.0. Results: TSC1/TSC2 gene mutations were present in all 24 patients, all of whom achieved a significant reduction in TSC-RAML volume within the initial 6-month induction therapy period, and exhibited volume stabilization during the low-dose maintenance therapy treatment period without any instances of TSC-RAML regrowth. Adverse events (AEs) were significantly less severe and less frequent over the course of maintenance therapy relative to standard therapy. Conclusions: Low-dose everolimus maintenance therapy represents an effective approach to achieving TSC-RAML control following a minimum of 6 months of full-dose induction therapy, and may be associated with decreases in everolimus-related AE frequency and severity.
    Keywords:  everolimus; low-dose maintenance therapy; renal angiomyolipoma; safety; tuberous sclerosis complex
    DOI:  https://doi.org/10.3389/fmed.2021.744050
  10. Sleep Med. 2021 Dec 01. pii: S1389-9457(21)00572-4. [Epub ahead of print]89 65-70
    Sleep disorders and neuropsychiatric disorders in a pediatric sample of tuberous sclerosis complex: a questionnaire-based study.
    Romina Moavero, Alessandra Voci, Francesca La Briola, Sara Matricardi, Irene Toldo, Maria Margherita Mancardi, Susanna Negrin, Tullio Messana, Luigi Mazzone, Massimiliano Valeriani, Paolo Curatolo, Oliviero Bruni.
      OBJECTIVE AND BACKGROUND: Sleep disorders (SD) are very common in childhood, especially in certain genetic syndromes. Tuberous Sclerosis Complex (TSC) is a genetic syndromesassociated with a high rate of SD, although these are still under-recognized. The aim of this study was to assess the prevalence of SD in TSC, and to evaluate the relationship between sleep, epilepsy and TSC-associated neuropsychiatric disorders (TAND).METHODS: We administered the Sleep Disturbance Scale for Children (SDSC) and the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) to parents of 177 children with TSC referring to different Italian centers. We also collected information on epilepsy and TAND.
    RESULTS: SDSC score was positive in 59.3% of patients, being positive in 30.4% of patients without and in 63.6% of those with epilepsy (p = 0.005). However, in a multivariate logistic model considering antiseizure medications and nocturnal seizures, epilepsy ceased to be a significant risk factor for positive SDSC (OR = 2.4; p = 0.17). As for TAND, SDSC was positive in 67.9% of patients with and in 32.5% of those without TAND (p < 0.001). After adding in a multivariate logistic model active epilepsy, age, and pharmacotherapies, TAND continued to be a significant risk factor for positive SDSC (p = 0.01, OR = 1.11).
    CONCLUSIONS: Our results revealed a high prevalence of SD in children with TSC. Epilepsy didn't increase the risk for SD, while a very strong association was found with TAND. An early detection of SD is of utmost importance in order to plan an individualized treatment, that in some cases might also ameliorate behavior and attention.
    Keywords:  Autism; Epilepsy; Neuropsychiatric disorders; Sleep; Sleep disorders; Tuberous sclerosis
    DOI:  https://doi.org/10.1016/j.sleep.2021.11.010
  11. Int J Cardiovasc Imaging. 2021 Dec 12.
    Myocardial fatty foci: not all echogenic myocardial lesions in Tuberous sclerosis are rhabdomyomas.
    Vineeta Ojha, Sravan Nagulakonda, Amarinder Singh Malhi, Siddharthan Deepti, Priya Jagia.
      
    DOI:  https://doi.org/10.1007/s10554-021-02491-x
  12. J Indian Assoc Pediatr Surg. 2021 Nov-Dec;26(6):26(6): 380-392
    Benign Renal Tumors in Pediatric Age Group: Retrospective Analysis.
    Prema Menon, Katragadda Lakshmi Narasimha Rao, Saalim Nazki, Saswati Behera, Kirti Gupta, Ram Samujh, Shailesh Solanki, Akshay Saxena, Deepak Bansal, Amita Trehan.
      Background: Benign renal tumors are extremely rare and were studied here. This series also includes a renal teratoma in a horseshoe kidney, probably only the second in the pediatric literature.Materials and Methods: Retrospective review of children with benign renal tumors operated between 2006 and 2018 at one center.
    Results: Twelve patients (M:F ratio 10:2), age range 3 weeks (31-week gestation) to 13 years presented with large palpable renal swelling (n = 12) and hematuria (n = 3). Computed tomography (CT) scan showed features typical of the tumor. Final histopathology (age group [mean]) showed: multilocular cystic nephroma (MLCN) - n = 5 (41.7%), (11-16 months [13.6]); congenital mesoblastic nephroma (CMN) - n = 4 (33.3%) (classic 1, cellular 3) (0.75-5 months [2.125]); mature cystic teratoma - n = 1 (8.3%): (48 months, in a horseshoe kidney), and angiomyolipoma (AML) - n = 2 (16.7%) (144 months [sporadic] and 156 months [tuberous sclerosis]) One patient with cystic teratoma with no calcification on CT scan received pre-operative chemotherapy as fine-needle aspiration cytology (FNAC) reported malignant small blue cell tumor. Nephroureterectomy with Gerota's fascia could be done easily in all without intraoperative complications. Delay in presentation in MLCN and CMN led to increased symptoms and CT scan changes. All patients did well in 1.5-12 years (median 3 years) follow-up including cellular mesoblastic nephroma.
    Conclusions: Benign renal tumors often occur in specific age groups but may overlap that of Wilms tumor. Proper interpretation of clinical presentation, CT scan, and FNAC findings help in avoiding preoperative chemotherapy. Upfront nephroureterectomy is curative. Histopathological findings decide further treatment. Children with AML and tuberous sclerosis need lifelong follow-up.
    Keywords:  Angiomyolipoma; congenital mesoblastic nephroma; kidney; multilocular cystic nephroma; nephroureterectomy; teratoma
    DOI:  https://doi.org/10.4103/jiaps.JIAPS_214_20
  13. PLoS Comput Biol. 2021 Dec 13. 17(12): e1009683
    Roles of mTOR in thoracic aortopathy understood by complex intracellular signaling interactions.
    Ana C Estrada, Linda Irons, Bruno V Rego, Guangxin Li, George Tellides, Jay D Humphrey.
      Thoracic aortopathy-aneurysm, dissection, and rupture-is increasingly responsible for significant morbidity and mortality. Advances in medical genetics and imaging have improved diagnosis and thus enabled earlier prophylactic surgical intervention in many cases. There remains a pressing need, however, to understand better the underlying molecular and cellular mechanisms with the hope of finding robust pharmacotherapies. Diverse studies in patients and mouse models of aortopathy have revealed critical changes in multiple smooth muscle cell signaling pathways that associate with disease, yet integrating information across studies and models has remained challenging. We present a new quantitative network model that includes many of the key smooth muscle cell signaling pathways and validate the model using a detailed data set that focuses on hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and its inhibition using rapamycin. We show that the model can be parameterized to capture the primary experimental findings both qualitatively and quantitatively. We further show that simulating a population of cells by varying receptor reaction weights leads to distinct proteomic clusters within the population, and that these clusters emerge due to a bistable switch driven by positive feedback in the PI3K/AKT/mTOR signaling pathway.
    DOI:  https://doi.org/10.1371/journal.pcbi.1009683
This page is being maintained by Thomas Krichel. It was last updated on 2021‒12‒19 at 10:07:26.