bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2021‒04‒11
eleven papers selected by
Marti Cadena Sandoval

  1. Genet Mol Biol. 2021 ;pii: S1415-47572021000300103. [Epub ahead of print]44(2): e20200014
      Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by germline mutations in TSC1 or TSC2 genes, which leads to the hyperactivation of the mTORC1 pathway, an important negative regulator of autophagy. This leads to the development of hamartomas in multiple organs. The variability in symptoms presents a challenge for the development of completely effective treatments for TSC. One option is the treatment with mTORC1 inhibitors, which are targeted to block cell growth and restore autophagy. However, the therapeutic effect of rapamycin seems to be more efficient in the early stages of hamartoma development, an effect that seems to be associated with the paradoxical role of autophagy in tumor establishment. Under normal conditions, autophagy is directly inhibited by mTORC1. In situations of bioenergetics stress, mTORC1 releases the Ulk1 complex and initiates the autophagy process. In this way, autophagy promotes the survival of established tumors by supplying metabolic precursors during nutrient deprivation; paradoxically, excessive autophagy has been associated with cell death in some situations. In spite of its paradoxical role, autophagy is an alternative therapeutic strategy that could be explored in TSC. This review compiles the findings related to autophagy and the new therapeutic strategies targeting this pathway in TSC.
  2. Cell Mol Life Sci. 2021 Apr 08.
      The mechanistic target of rapamycin complex 1 (mTORC1) is an important regulator of cellular metabolism that is commonly hyperactivated in cancer. Recent cancer genome screens have identified multiple mutations in Ras-homolog enriched in brain (Rheb), the primary activator of mTORC1 that might act as driver oncogenes by causing hyperactivation of mTORC1. Here, we show that a number of recurrently occurring Rheb mutants drive hyperactive mTORC1 signalling through differing levels of insensitivity to the primary inactivator of Rheb, tuberous sclerosis complex. We show that two activated mutants, Rheb-T23M and E40K, strongly drive increased cell growth, proliferation and anchorage-independent growth resulting in enhanced tumour growth in vivo. Proteomic analysis of cells expressing the mutations revealed, surprisingly, that these two mutants promote distinct oncogenic pathways with Rheb-T23M driving an increased rate of anaerobic glycolysis, while Rheb-E40K regulates the translation factor eEF2 and autophagy, likely through differential interactions with 5' AMP-activated protein kinase (AMPK) which modulate its activity. Our findings suggest that unique, personalized, combination therapies may be utilised to treat cancers according to which Rheb mutant they harbour.
    Keywords:  AMPK; PKM; Rheb; TSC; eEF2; mTOR
  3. Rev Med Interne. 2021 Apr 06. pii: S0248-8663(21)00061-8. [Epub ahead of print]
      Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects different organs and caused by loss-of-function mutations in one of two genes: TSC1 or TSC2. TSC1 or TSC2 gene mutation lead to dysfunction of hamartin or tuberin, respectively. Hamartin and tuberin form a protein complex that helps regulate cellular proliferation. These proteins form a complex that constitutively inhibits the mammalian target of rapamycin (mTOR) signaling pathway, leading to permanent activation of mTOR signaling within all TSC-associated lesions. Major features of TSC include tumors of the brain, skin, heart, lungs and kidneys, seizures and TSC-associated neuropsychiatric disorders, which can include autism spectrum disorder and cognitive disability. These disorders are usually diagnosed in children and adults. Specific guidelines for diagnosis, surveillance, and management have been proposed by the International Tuberous Sclerosis Complex Consensus Group. Several randomized controlled trials led to regulatory approval of the use of mTOR inhibitors for the treatment of renal angiomyolipomas, brain subependymal giant cell astrocytomas, refractory epilepsy and pulmonary lymphangioleiomyomatosis.
    Keywords:  Angiomyolipoma; Angiomyolipomes; Epilepsy; Genetic; Génétique; Inhibiteurs de mTOR; MTOR inhibitor.; Sclérose tubéreuse de Bourneville; Tuberous sclerosis complex; épilepsie
  4. Pediatr Dev Pathol. 2021 Apr 07. 10935266211006078
      Meningioma is the most common radiation-induced brain neoplasm, usually occurring after a latency of 20 - 35 years, with multiplicity in 10% of cases. Radiation-induced meningiomas (RIMs) have not previously been reported in patients with tuberous sclerosis complex (TSC), unlike their well-known occurrence in other familial tumor predisposition syndrome patients. We report a TSC patient who developed numerous intracranial meningiomas twenty five year after radiation therapy for subependymal giant cell astrocytoma (SEGA). Autopsy examination showed innumerable, coalescent, benign, meningothelial meningiomas, WHO grade 1, ranging in size from 0.2 cm to 3.3 cm. Autopsy also showed small residual SEGA, radiation-induced cerebral vasculopathy, and classic TSC features including several small subependymal nodules ("candle gutterings"), white matter radial heterotopia, facial angiofibromas, dental enamel pitting, one ash leaf spot, and multiple hepatic and renal angiomyolipomas. Next-generation sequencing analysis utilizing a 500+ gene cancer panel demonstrated chromosomal loss involving the majority of chromosome 22, including the NF2 gene locus, as well as a truncating nonsense mutation in TSC1 p. R509*. While TSC patients rarely require radiation therapy, this striking case suggests that patients with TSC should be monitored closely if cranial therapeutic radiation is administered.
    Keywords:  calvarium; familial tumor predisposition syndrome; radiation therapy; skull base
  5. Genet Med. 2021 Apr 08.
      PURPOSE: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI.METHODS: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies.
    RESULTS: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI.
    CONCLUSION: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex.
  6. Balkan J Med Genet. 2020 Nov;23(2): 93-98
      Tuberous sclerosis complex (TSC) is an autosomal-dominant multi system disorder. The genetic basis of the disorder is mutations in the TSC1 or TSC2 gene, which leads to over activation of the mammalian target of rapamycin (mTOR) protein complex and results in development of benign tumors in different body systems such as brain, skin, lungs and kidney. The mTOR inhibitors are presently the main treatment option for patients with TSC. We here report a 21-year female patient with large bilateral angiomyolipoma (AML) in both kidneys with longest diameter more than 12.3 cm and subependymal giant cell astrocytoma (SEGA). Treatment with everolimus (EVE) was initiated at a dose of 10.0 mg/day and continued during the following 3 years. Magnetic resonance imaging (MRI) was performed before treatment with everolimus was initiated, and consequently at 12 and 36 months for follow-up of the efficacy of the treatment. After 3 years, the total size of largest AML decreased by ~24.0% in the longest diameter. A reduction of the total size of SEGA was also observed. The most common adverse effect of treatment was stomatitis grades 3 to 4 and one febrile episode associated with skin rash that required a reduced dose of EVE. In conclusion, the everolimus treatment improved even such a large renal AML and the effect persisted during the long-term administration with a small number of adverse effects. A positive effect was observed on the brain tumor as well.
    Keywords:  Angiomyolipoma (AML); Everolimus (EVE); Subependymal giant cell astrocytoma (SEGA); Tuberous sclerosis complex (TSC)
  7. Front Neurol. 2021 ;12 630378
      This non-interventional post-authorisation safety study (PASS) assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) who participated in the TuberOus SClerosis registry to increase disease Awareness (TOSCA) clinical study and received everolimus for the licensed indications in the European Union. The rate of adverse events (AEs), AEs that led to dose adjustments or treatment discontinuation, AEs of potential clinical interest, treatment-related AEs (TRAEs), serious AEs (SAEs), and deaths were documented. One hundred seventy-nine patients were included in the first 5 years of observation; 118 of 179 patients had an AE of any grade, with the most common AEs being stomatitis (7.8%) and headache (7.3%). AEs caused dose adjustments in 56 patients (31.3%) and treatment discontinuation in nine patients (5%). AEs appeared to be more frequent and severe in children. On Tanner staging, all patients displayed signs of age-appropriate sexual maturation. Twenty-two of 106 female (20.8%) patients had menstrual cycle disorders. The most frequent TRAEs were stomatitis (6.7%) and aphthous mouth ulcer (5.6%). SAEs were reported in 54 patients (30.2%); the most frequent SAE was pneumonia (>3% patients; grade 2, 1.1%, and grade 3, 2.8%). Three deaths were reported, all in patients who had discontinued everolimus for more than 28 days, and none were thought to be related to everolimus according to the treating physicians. The PASS sub-study reflects the safety and tolerability of everolimus in the management of TSC in real-world routine clinical practice.
    Keywords:  TOSCA; everolimus; mammalian target of rapamycin; post-authorization safety study; tuberous sclerosis complex
  8. Seizure. 2021 Mar 25. pii: S1059-1311(21)00098-4. [Epub ahead of print]88 45-52
      OBJECTIVE: To identify prognostic factors and long-term seizure outcomes for patients with tuberous sclerosis complex (TSC) who underwent resective treatment for epilepsy.METHODS: We enrolled 81 patients with TSC who had undergone resective epilepsy surgery at Sanbo Brain Hospital, Capital Medical University, between April 2004 and June 2019. We estimated cumulative probability of remaining seizure-free and plotted survival curves. Variables were compared using Mann-Whitney U, Pearson's correlation, continuity correction, and Fisher's exact chi-square tests. Prognostic predictors were analysed using log-rank (Mantel-Cox) tests and Cox regression models.
    RESULTS: At the last follow-up, 48 (59.3%) patients were classified as International League Against Epilepsy Class 1 (including 14 patients who had seizures <3 times postoperatively on the same or different day and were seizure-free at all other times). The estimated cumulative probability of remaining seizure-free postoperatively was 69.0% (95% confidence interval [CI] 58.8-79.2%), 61.9% (95% CI 51.1-72.7%), and 55.0% (95% CI 42.8-67.2%) at 2, 5, and 10 years, respectively. The mean time of remaining seizure-free was 7.24 ± 0.634 years (95% CI 6.00-8.49); en bloc resection was an essential positive predictor of postoperative seizure freedom, as was age at seizure onset, regional interictal video-electroencephalography pattern, and temporal lobe surgery. The longer the seizure-free time, the less likely a relapse. Patients who postoperatively experienced seizures remained likely to recover.
    CONCLUSIONS: We demonstrated the efficacy of surgical treatment for patients with TSC and intractable epilepsy. Detailed perioperative tests are a reliable predictor of postoperative seizure freedom.
    Keywords:  Age at seizure onset; En bloc resection; Magnetic source imaging; Seizure outcome; Temporal lobe epilepsy; Video-electroencephalography
  9. Expert Rev Neurother. 2021 Apr 09.
      Introduction: Focal Cortical Dysplasias (FCDs) represent the most common etiology in pediatric drug-resistant focal epilepsies undergoing surgical treatment. The localization, extent and histopathological features of FCDs are considerably variable. Somatic mosaic mutations of genes that encode proteins in the PI3K-AKTmTOR pathway, which also includes the tuberous sclerosis associated genes TSC1 and TSC2, have been implicated in FCD type II in a substantial subset of patients. Surgery is the principal therapeutic option for FCD-related epilepsy. Advanced neurophysiological and neuroimaging techniques have improved surgical outcome and reduced the risk for postsurgical deficits. Pharmacological MTOR inhibitors are being tested in clinical trials and might represent an example of personalized treatment of epilepsy based on the known mechanisms of disease, used alone or in combination with surgery.Areas covered: This review will critically analyze the advances in the diagnosis and treatment of FCDs, with special focus on the novel therapeutic options prompted by better understanding of their pathophysiology.Expert opinion: Focal cortical dysplasia is a main cause of drug-resistant epilepsy, especially in children. Novel, personalized approaches are needed to more effectively treat FCD-related epilepsy and its cognitive consequences.
    Keywords:  EEG; Focal cortical dysplasia; MRI; MTOR pathway; surgery
  10. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2021 Apr 10. 38(4): 363-365
      OBJECTIVE: To analyze the clinical features of a Chinese pedigree affected with tuberculosis sclerosis and explore its molecular pathogenesis.METHODS: Clinical data of the proband and members of his pedigree were collected. Whole exome sequencing was carried out to detect variants of the TSC1 and TSC2 genes. Candidate variants was verified by Sanger sequencing and bioinformatic analysis.
    RESULTS: The proband and his mother, who also had mild features of tuberous sclerosis, were found to harbor a novel heterozygous c.4183C>T (p.Q1395X) variant of the TSC2 gene, which was absent in the 4 healthy relatives. Bioinformatic analysis suggested the variant to be likely pathogenic.
    CONCLUSION: The heterozygous c.4183C>T (p.Q1395X) variant of the TSC2 gene probably underlay the disease in this pedigree. Above finding has expanded the spectrum of TSC2 gene variants. The more severe symptoms in the proband may be attributed to phenotypic heterogeneity of this disease.
  11. Sci Rep. 2021 Apr 08. 11(1): 7787
      Aberrant activation of the PI3K/AKT/mTOR pathway is attributed to the pathogenesis of oral squamous cell carcinoma (OSCC). In recent years, increasing evidence suggests the involvement of microRNAs (miRNAs) in oral carcinogenesis by acting as tumor suppressors or oncogenes. TSC1, as a component of the above pathway, regulates several cellular functions such as cell proliferation, apoptosis, migration and invasion. Downregulation of TSC1 is reported in oral as well as several other cancers and is associated with an unfavourable clinical outcome in patients. Here we show that oncogenic miR-130a binds to the 3'UTR of TSC1 and represses its expression. MiR-130a-mediated repression of TSC1 increases cell proliferation, anchorage independent growth and invasion of OSCC cells, which is dependent on the presence of the 3'UTR in TSC1. We observe an inverse correlation between the expression levels of miR-130a and TSC1 in OSCC samples, suggesting that their interaction is physiologically relevant. Delivery of antagomiR-130a to OSCC cells results in a significant decrease in xenograft size. Taken together, the findings of the study indicate that miR-130a-mediated TSC1 downregulation is not only a novel mechanism in OSCC, but also the restoration of TSC1 levels by antagomiR-130a may be a potential therapeutic strategy for the treatment of OSCC.