bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2021‒06‒06
fifteen papers selected by
Marti Cadena Sandoval
metabolic-signalling.eu


  1. Orphanet J Rare Dis. 2021 Jun 02. 16(1): 250
      BACKGROUND: Tuberous sclerosis complex (TSC) is a monogenetic, multisystem disorder characterized by benign growths due to TSC1 or TSC2 mutations. This German multicenter study estimated the costs and related cost drivers associated with organ manifestations in adults with TSC.METHODS: A validated, three-month, retrospective questionnaire assessed the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket (OOP), and nursing care-level costs among adult individuals with TSC throughout Germany from a societal perspective (costing year: 2019).
    RESULTS: We enrolled 192 adults with TSC (mean age: 33.4 ± 12.7 years; range: 18-78 years, 51.6% [n = 99] women). Reported TSC disease manifestations included skin (94.8%) and kidney and urinary tract (74%) disorders, epilepsy (72.9%), structural brain defects (67.2%), psychiatric disorders (50.5%), heart and circulatory system disorders (50.5%), and lymphangioleiomyomatosis (11.5%). TSC1 and TSC2 mutations were reported in 16.7% and 25% of respondents, respectively. Mean direct health care costs totaled EUR 6452 (median EUR 1920; 95% confidence interval [CI] EUR 5533-7422) per patient over three months. Medication costs represented the major direct cost category (77% of total direct costs; mean EUR 4953), and mechanistic target of rapamycin (mTOR) inhibitors represented the largest share (68%, EUR 4358). Mean antiseizure drug (ASD) costs were only EUR 415 (6%). Inpatient costs (8%, EUR 518) and outpatient treatment costs (7%; EUR 467) were important further direct cost components. The mean care grade allowance as an approximator of informal nursing care costs was EUR 929 (median EUR 0; 95% CI EUR 780-1083) over three months. Mean indirect costs totaled EUR 3174 (median EUR 0; 95% CI EUR 2503-3840) among working-age individuals (< 67 years in Germany). Multiple regression analyses revealed mTOR inhibitor use and persistent seizures as independent cost-driving factors for total direct costs. Older age and disability were independent cost-driving factors for total indirect costs, whereas epilepsy, psychiatric disease, and disability were independent cost-driving factors for nursing care costs.
    CONCLUSIONS: This three-month study revealed substantial direct healthcare, indirect healthcare, and medication costs associated with TSC in Germany. This study highlights the spectrum of organ manifestations and their associated treatment needs in the German healthcare setting.
    TRIAL REGISTRATION: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045 .
    Keywords:  Angiomyolipoma; Anticonvulsant; Costs; Epilepsy; Genetics; MTOR inhibitor; Seizure; Sociodemographic characteristics; Subependymal giant cell astrocytoma; TSC
    DOI:  https://doi.org/10.1186/s13023-021-01838-w
  2. J Neurol Sci. 2021 May 21. pii: S0022-510X(21)00200-8. [Epub ahead of print]427 117506
      Epilepsy surgery is recommended in selected patients with Tuberous Sclerosis Complex (TSC). However, reports on predictive factors of seizure outcome are variable. Here we report on seizure and cognitive outcome of 35 TSC patients who received surgery for refractory epilepsy in 7 Italian centers over a period of 22 years (1997-2019). The rate of seizure-free individuals at last follow-up (mean 7.5 years, range 1-21 years) was 51%. Patients with longer follow-up (≥10 years) had a lower rate of Engel I outcome (11.1%) than those who received surgery in the last 10 years (65.4%, p = 0.003). Factors associated with Engel II, III, IV outcome in our cohort included: high number of cortical tubers (≥5); presence of subependymal nodules (SENs); seizure onset before age 1 year; and multifocal interictal epileptic discharges (IEDs) on electroencephalogram (EEG). A subset of patients evaluated with Vineland Adaptive Behaviour Scales (VABS) showed developmental gains, in line with their developmental trajectories, but no improvement in standard scores after surgery was noted. Our study demonstrates that the rates of successful seizure outcome of epilepsy surgery in TSC have improved in the last 10 years. More than half of the patients achieved seizure freedom, and a high proportion of affected individuals experienced a reduction in seizure burden and in antiseizure medications. A comprehensive assessment after surgery should be performed in TSC patients to evaluate the overall neurodevelopmental outcome, as measures that are based only on seizure control do not adequately identify the benefits of surgery on global functioning in these patients.
    Keywords:  Engel class; Epilepsy; Epilepsy surgery; Refractory epilepsy; Tuberous sclerosis complex
    DOI:  https://doi.org/10.1016/j.jns.2021.117506
  3. Int J Environ Res Public Health. 2021 May 05. pii: 4907. [Epub ahead of print]18(9):
      BACKGROUND: Cardiac rhabdomyomas (CRs) are the earliest sign of tuberous sclerosis complex (TSC). Most of them spontaneously regress after birth. However, multiple and/or large tumors may result in heart failure or cardiac arrhythmia. Recently, the attempts to treat CRs with mTOR inhibitors (mTORi) have been undertaken. We reviewed the current data regarding the effectiveness and safety of mTORi in the treatment of CRs in children with TSC.METHODS: The review was conducted according to the PRISMA guidelines. Medline, Embase, Cochrane library, and ClinicalTrial.gov databases were searched for original, full-text articles reporting the use of mTORi (everolimus or sirolimus) in the treatment of CRs in children with TSC.
    RESULTS: Thirty articles describing 41 patients were identified (mostly case reports, no randomized or large cohort studies). Thirty-three children (80.5%) had symptomatic CRs and mTORi therapy resulted in clinical improvement in 30 of them (90.9%). CRs size reduction was reported in 95.1%. Some CRs regrew after mTORi withdrawal but usually without clinical symptoms recurrence. The observed side effects were mostly mild.
    CONCLUSIONS: mTORi may be considered as a temporary and safe treatment for symptomatic CRs in children with TSC, especially in high-risk or inoperable tumors. However, high-quality, randomized trials are still lacking.
    Keywords:  cardiac rhabdomyoma; children; everolimus; heart; mTOR inhibitor; sirolimus; tuberous sclerosis complex; tumor
    DOI:  https://doi.org/10.3390/ijerph18094907
  4. Epilepsy Behav. 2021 Jun 01. pii: S1525-5050(21)00266-3. [Epub ahead of print]121(Pt A): 108032
      We studied mortality in tuberous sclerosis complex (TSC) by analyzing data from the Tuberous Sclerosis Alliance Natural History Database of 2233 patients from 18 United States TSC centers. Among 31 decedents with data; mean age of death was 29 years. Cause of death could be determined in 26 cases: 11 definitely related to TSC, 14 possibly related to TSC, and 1 unrelated to TSC. Causes of death included SUDEP in 11 (35.5%; Definite (5), Probable (4), Possible (2)), respiratory conditions in 6 (23.1%; lymphangiomyelomatosis in one), tumors in 3 (11.5%), suicide in 2 (7.7%), cardiopulmonary in 2 (7.7%), shunt malfunction in one, and drowning in one. For SUDEP cases, mean age of epilepsy onset was 7 months and 10/11 were treated with multiple anti-seizure medications (ASMs) at death; 7 had intractable epilepsy and 3 were controlled with ASMs. Patients with TSC and their families should be counseled about ASM adherence and lifestyle factors, and the potential role of nocturnal supervision or seizure detection devices to prevent SUDEP.
    Keywords:  Mortality; Sudden unexpected death in epilepsy (SUDEP); Tuberous sclerosis complex
    DOI:  https://doi.org/10.1016/j.yebeh.2021.108032
  5. NMR Biomed. 2021 Jun 01. e4565
      Few in vivo studies have focused on the perivenous association of tubers and iron deposition in the deep gray nuclei in patients with tuberous sclerosis complex (TSC). We investigated this possible relationship in TSC patients using susceptibility weighted imaging (SWI) at 7 T. SWI with high spatial resolution and enhanced sensitivity was performed on 11 TSC patients in comparison with 15 age- and sex-matched healthy controls. The relationship between tubers and veins was evaluated. In addition, the phase images of SWI were processed to produce local field shift (LFS) maps to quantify iron deposition. The mean LFS in the deep gray nuclei was compared between the TSC patients and healthy controls using a covariance analysis. Venous involvement was observed in 211 of the 231 (91.3%) cortical tubers on SWI. The slender tubers often oriented around the long axis of penetrating veins, possibly because cortical tubers typically developed and/or migrated along venous vasculatures. A significant difference in LFS of the thalamus was detected between the TSC patients and healthy controls (3.36 ± 0.50 versus 3.01 ± 0.39, p < 0.01). The new in vivo imaging features observed at 7 T provide valuable insights into the possible venous association of TSC lesions and iron accumulation in the deep gray nuclei. Our results may lead to a better understanding of the pathological changes involved in TSC under in vivo conditions.
    Keywords:  7T MRI; iron deposition; tuberous sclerosis complex; venous involvement
    DOI:  https://doi.org/10.1002/nbm.4565
  6. Biochemistry. 2021 Jun 03.
      Tuberous sclerosis protein complex (pTSC) nucleates a proteinaceous signaling hub that integrates information about the internal and external energy status of the cell in the regulation of growth and energy consumption. Biochemical and cryo-electron microscopy studies of recombinant pTSC have revealed its structure and stoichiometry and hinted at the possibility that the complex may form large oligomers. Here, we have partially purified endogenous pTSC from fasted mammalian brains of rat and pig by leveraging a recombinant antigen binding fragment (Fab) specific for the TSC2 subunit of pTSC. We demonstrate Fab-dependent purification of pTSC from membrane-solubilized fractions of the brain homogenates. Negative stain electron microscopy of the samples purified from pig brain demonstrates rod-shaped protein particles with a width of 10 nm, a variable length as small as 40 nm, and a high degree of conformational flexibility. Larger filaments are evident with a similar 10 nm width and a ≤1 μm length in linear and weblike organizations prepared from pig brain. Immunogold labeling experiments demonstrate linear aggregates of pTSC purified from mammalian brains. These observations suggest polymerization of endogenous pTSC into filamentous superstructures.
    DOI:  https://doi.org/10.1021/acs.biochem.1c00269
  7. Front Oncol. 2021 ;11 691996
      Tuberous sclerosis complex is a genetic disorder characterized by facial angiofibromas, intellectual disability, epilepsy, and tumor formation in multiple organs, including the kidney. Renal cell carcinoma occurs in 2%-4% of patients with tuberous sclerosis complex, often developing multiply and bilaterally. Renal cell carcinoma associated with this genetic disorder may include complex tumor heterogeneity caused by the spatially different mutational landscape. Herein, we report the case of a female patient with tuberous sclerosis complex who developed multiple renal tumors. A 44-year-old female patient with tuberous sclerosis complex developed three different histological types of tumor-angiomyolipoma, clear cell renal cell carcinoma, and papillary renal cell carcinoma-in the left kidney at first renal cell carcinoma recurrence. The papillary renal cell carcinoma was morphologically atypical, indicating that its occurrence was associated with the genetic disorder. Furthermore, whole-exome sequencing revealed distinct patterns of somatic mutation in the three tumor types, and the atypical papillary renal cell carcinoma possessed a different mutational landscape than that of typical papillary renal cell carcinomas. Our findings indicate that tumors associated with tuberous sclerosis complex may be diagnosed with careful pathological examination. Furthermore, somatic mutation profiles of these tumors revealed their unique features, providing important information for further understanding the mechanism of multiple tumor development in patients with tuberous sclerosis complex.
    Keywords:  cancer gene; papillary renal cell carcinoma; renal cell carcinoma; tuberous sclerosis complex; whole-exome sequencing
    DOI:  https://doi.org/10.3389/fonc.2021.691996
  8. J Int Med Res. 2021 May;49(5): 3000605211016761
      Talaromyces marneffei is a rare dimorphic pathogenic fungus that can induce severe infections in human immunodeficiency virus (HIV)-infected patients. However, such infections have also been reported in non-HIV hosts. This current case report describes a very rare case of a T. marneffei pulmonary infection in an HIV-negative patient with a mutation in the tuberous sclerosis complex subunit 2 (TSC2) gene. A 24-year-old male patient presented with cough and expectoration for 6 months. Computed tomography showed multiple ground-glass opacities and cystic and cavitated lesions in both lungs. Next generation sequencing (NGS) of the bronchoalveolar lavage fluid was performed to confirm T. marneffei pulmonary infection. The results were further verified using bronchoscopy specimen cultures. This was an HIV-negative patient without a travel history to endemic zones and his blood exon sequencing results showed a mutation in the TSC2 gene. To date, he has recovered well with voriconazole therapy. In summary, patients with TSC2 mutations that induce bronchopulmonary dysplasia may be potential hosts for T. marneffei. Early and timely diagnosis is important for improving prognosis. NGS plays a critical role in the diagnosis of T. marneffei pulmonary infection.
    Keywords:  HIV-negative; TSC2; Talaromyces marneffei; pulmonary infection
    DOI:  https://doi.org/10.1177/03000605211016761
  9. Anticancer Res. 2021 Jun;41(6): 3029-3036
      BACKGROUND: Malignant triton tumor (MTT) is a rare subtype of malignant peripheral nerve sheath tumor with additional rhabdomyolysis differentiation that shows rapid progression and poor clinical outcomes.CASE REPORT: We report the case of an adult male with a metastatic MTT. Despite extensive counseling, the patient initially refused recommended treatment. Upon disease progression, the patient was admitted to our institution and multiple distant organ metastases were found. The patient underwent an above-knee amputation followed by palliative chemotherapy. The patient died a few months later due to rapid disease progression.
    CONCLUSION: To our knowledge, this is the first report of a case of MTT with multiple splenic metastases. We also describe the first finding of a frame-shift mutation in the tuberous sclerosis complex 2 (TSC2) gene in a patient with MTT. Because of limited clinical experience and the lack of clinical trials, the effects of chemotherapy and radiation therapy for MTT remain controversial. However, given the aggressive nature of these tumors and the tendency for early recurrence and metastasis, prompt diagnosis and early surgical treatment are crucial for the best outcomes.
    Keywords:  Malignant triton tumor; Schwann cell tumor; chemotherapy; neurofibroma; peripheral nerve tumor
    DOI:  https://doi.org/10.21873/anticanres.15085
  10. Orphanet J Rare Dis. 2021 May 31. 16(1): 243
      BACKGROUND AND OBJECTIVE: Tuberous sclerosis (TS) is a condition whose manifestations in childhood have been extensively described, but whose presentation in adults is less well known. This study describes the clinical and genetic characteristics, therapeutic management and quality of life of a cohort of adult patients with TS. A comparative study of the characteristics of patients diagnosed in childhood and adulthood is also carried out.MATERIAL AND METHODS: This observational, retrospective, cross-sectional study included a large cohort of adult patients (≥ 16 years old) followed for 5 years in a specific rare diseases unit.
    RESULTS: Fifty-seven patients with a diagnosis of tuberous sclerosis were included, more than 50% of whom were diagnosed as adults. The mean age of the patients was 42 years (20-86). The central nervous system was the main area affected (97%), followed by the skin (80.7%) and kidneys (73%). The most frequent genetic alteration was a mutation in the TSC2 gene (47.7%). Among patients diagnosed in adulthood, there was less neurological involvement, with less frequency of epileptic seizures (30.8% vs 60.79% of patients diagnosed in childhood) and astrocytomas (3.8% vs 53.6%), less intellectual disability (11.5% vs 71.4%) and less expressiveness of the condition. 42% of patients were treated with mTOR pathway inhibitors, and presence of an angiomyolipoma was the main indication. In a quality-of-life analysis, the means of the summary indices were below the scores of the average Spanish population: (47.42 (SD ± 9.82) on the physical health scale, 45.61 (SD ± 7.99) on the mental health scale) versus 50 (SD ± 10) for the general population.
    CONCLUSIONS: Up to 50% of adult patients with TS were diagnosed in adulthood, and the condition is less severe with less frequent epileptic seizures and intellectual disability. 42% require treatment with mTOR inhibitors, in most cases due to the presence of AMLs. The quality of life of adult patients with TS is diminished compared to the general population.
    Keywords:  Adult; Multidisciplinary unit; Quality of life; Tuberous sclerosis
    DOI:  https://doi.org/10.1186/s13023-021-01878-2
  11. Autophagy. 2021 Jun 04.
      Target of rapamycin complex 1 (TORC1) promotes cellular anabolism and suppresses macroautophagy/autophagy. In mammalian cells starved of amino acid, the GATOR1 complex, a negative regulator of TORC1, is released from its inhibitor GATOR2 and inactivates TORC1. We have recently identified the evolutionarily conserved GATOR2 components in fission yeast including Sea3, an ortholog of mammalian WDR59, but, unexpectedly, Sea3 acts as a part of GATOR1 to suppress TORC1. Moreover, fission yeast GATOR1 is not required for the amino-acid starvation-induced TORC1 attenuation, which is instead mediated by the Gcn2 pathway. Conversely, absence of a nitrogen source suppresses TORC1 in a manner dependent on GATOR1 as well as the Tsc1-Tsc2 complex, whose mammalian equivalent functions as a growth-factor sensitive TORC1 inhibitor. Thus, the evolutionarily conserved signaling modules are utilized differently between fission yeast and mammals to control TORC1 activity and autophagy.
    Keywords:  GATOR complex; Gcn2; Rag GTPase; TOR; TSC complex; autophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1938915
  12. J Mol Cell Cardiol. 2021 May 31. pii: S0022-2828(21)00110-3. [Epub ahead of print]
      RATIONALE: The nutrient sensing mechanistic target of rapamycin complex 1 (mTORC1) and its primary inhibitor, tuberin (TSC2), are cues for the development of cardiac hypertrophy. The phenotype of mTORC1 induced hypertrophy is unknown.OBJECTIVE: To examine the impact of sustained mTORC1 activation on metabolism, function, and structure of the adult heart.
    METHODS AND RESULTS: We developed a mouse model of inducible, cardiac-specific sustained mTORC1 activation (mTORC1iSA) through deletion of Tsc2. Prior to hypertrophy, rates of glucose uptake and oxidation, as well as protein and enzymatic activity of glucose 6-phosphate isomerase (GPI) were decreased, while intracellular levels of glucose 6-phosphate (G6P) were increased. Subsequently, hypertrophy developed. Transcript levels of the fetal gene program and pathways of exercise-induced hypertrophy increased. While hypertrophy did not progress to heart failure. We therefore examined the hearts of wild-type mice subjected to voluntary physical activity and observed early changes in GPI, followed by hypertrophy. Rapamycin prevented these changes in both models.
    CONCLUSION: Activation of mTORC1 in the adult heart triggers the development of a non-specific form of hypertrophy which is preceded by changes in cardiac glucose metabolism.
    Keywords:  Exercise; Glycolysis; Hypertrophy; Metabolism; mTORC1
    DOI:  https://doi.org/10.1016/j.yjmcc.2021.05.016
  13. Cancers (Basel). 2021 May 18. pii: 2441. [Epub ahead of print]13(10):
      Cathepsin K is a papain-like cysteine protease with high matrix-degrading activity. Among several cathepsins, cathepsin K is the most potent mammalian collagenase, mainly expressed by osteoclasts. This review summarizes most of the recent findings of cathepsin K expression, highlighting its role in renal tumors for diagnostic purposes and as a potential molecular target. Indeed, cathepsin K is a recognized diagnostic tool for the identification of TFE3/TFEB-rearranged renal cell carcinoma, TFEB-amplified renal cell carcinoma, and pure epithelioid PEComa/epithelioid angiomyolipoma. More recently, its expression has been observed in a subgroup of eosinophilic renal neoplasms molecularly characterized by TSC/mTOR gene mutations. Interestingly, both TSC mutations or TFE3 rearrangement have been reported in pure epithelioid PEComa/epithelioid angiomyolipoma. Therefore, cathepsin K seems to be a downstream marker of TFE3/TFEB rearrangement, TFEB amplification, and mTOR pathway activation. Given the established role of mTOR inhibitors as a pharmacological option in renal cancers, cathepsin K could be of use as a predictive marker of therapy response and as a potential target. In the future, uropathologists may implement the use of cathepsin K to establish a diagnosis among renal tumors with clear cells, papillary architecture, and oncocytic features.
    Keywords:  PEComa; TSC1/TSC2; angiomyolipoma; cathepsin K; differential diagnosis; mTOR pathway; predictive markers; renal cancers; translocation renal cell carcinoma
    DOI:  https://doi.org/10.3390/cancers13102441
  14. Int J Nanomedicine. 2021 ;16 3565-3578
      Background: Renal fibrosis is a chronic and progressive process affecting kidneys in chronic kidney disease (CKD). Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been shown to alleviate renal fibrosis and injury, but the mechanism of MSCs-Exo-induced renal protection remains unknown.Methods: In this study, MSCs were transfected with let-7i-5p antagomir (anti-let-7i-5p), and then exosomes were isolated from the transfected MSCs to deliver anti-let-7i-5p oligonucleotides to inhibit the level of let-7i-5p in kidney tubular epithelial cells (NRK-52E).
    Results: In both NRK-52E cells stimulated by TGF-β1 and the mouse kidneys after unilateral ureteral obstruction (UUO), we demonstrated increased level of let-7i-5p. In addition, MSCs-Exo can deliver anti-let-7i-5p to reduce the level of let-7i-5p in NRK-52E cells and increase the expression of its target gene TSC1. Moreover, exosomal anti-let-7i-5p reduced extracellular matrix (ECM) deposition and attenuated epithelial-mesenchymal transition (EMT) process in transforming growth factor beta 1 (TGF-β1)-stimulated NRK-52E cells and in the kidneys of UUO-treated mice. Meanwhile, mice received exosomal anti-let-7i-5p displayed reduced renal fibrosis and improved kidney function when challenged with UUO. Furthermore, exosomal anti-let-7i-5p promoted the activation the tuberous sclerosis complex subunit 1/mammalian target of rapamycin (TSC1/mTOR) signaling pathway in vivo and in vitro.
    Conclusion: In conclusion, exosomal anti-let-7i-5p from MSCs exerts anti-fibrotic effects in TGF-β1-induced fibrogenic responses in NRK52E cells in vitro as well as in UUO-induced renal fibrosis model in vivo. These results provided a novel perspective on improving renal fibrosis by MSCs-Exo.
    Keywords:  chronic kidney disease; exosomes and microRNAs; mesenchymal stem cells; renal fibrosis
    DOI:  https://doi.org/10.2147/IJN.S299969
  15. Front Mol Neurosci. 2021 ;14 659856
      A common hypothesis explains autism spectrum disorder (ASD) as a neurodevelopmental disorder linked to excitatory/inhibitory (E/I) imbalance in neuronal network connectivity. Mutation of genes including Met and downstream signaling components, e.g., PTEN, Tsc2 and, Rheb are involved in the control of synapse formation and stabilization and were all considered as risk genes for ASD. While the impact of Met on glutamatergic synapses was widely appreciated, its contribution to the stability of inhibitory, GABAergic synapses is poorly understood. The stabilization of GABAergic synapses depends on clustering of the postsynaptic scaffolding protein gephyrin. Here, we show in vivo and in vitro that Met is necessary and sufficient for the stabilization of GABAergic synapses via induction of gephyrin clustering. Likewise, we provide evidence for Met-dependent gephyrin clustering via activation of mTOR. Our results support the notion that deficient GABAergic signaling represents a pathomechanism for ASD.
    Keywords:  TSC2; autism; gephyrin; proto-oncogene Met; synaptic connectivity
    DOI:  https://doi.org/10.3389/fnmol.2021.659856