bims-tubesc Biomed News
on Molecular mechanisms in tuberous sclerosis
Issue of 2021‒03‒28
ten papers selected by
Marti Cadena Sandoval

  1. Acta Neurol Scand. 2021 Mar 22.
      OBJECTIVES: Little is known about the evolution of epilepsy in individuals with tuberous sclerosis complex (TSC) in adulthood. This study aims at describing the characteristics of epilepsy in adult TSC patients attending a single multidisciplinary clinic.MATERIALS AND METHODS: We collected data about epilepsy (age at onset, seizure types, history of infantile spasms (IS), epilepsy diagnosis and outcome), genetic and neuroradiological findings, cognitive outcome and psychiatric comorbidities.
    RESULTS: Out of 257 adults with TSC, 183 (71.2%) had epilepsy: 121 (67.2%) were drug-resistant; 59 (32.8%) seizure-free, at a median age of 18 years. 22% of the seizure-free patients (13/59) discontinued medication. Median age at seizure onset was 9 months. Seventy-six patients (41.5%) had a history of IS. TSC2 pathogenic variants (p = 0.018), cortical tubers (p < 0.001) and subependymal nodules (SENs) (p < 0.001) were more frequent in those who developed epilepsy. Cognitive functioning was lower (p < 0.001) and psychiatric disorders more frequent (p = 0.001). We did not find significant differences regarding age, gender, mutation and tubers/SENs in seizure-free vs drug-resistant individuals. Intellectual disability (p < 0.001) and psychiatric disorders (p = 0.004) were more common among drug-resistant patients.
    CONCLUSIONS: Epilepsy in TSC can be a lifelong disorder, but one-third of individuals reach seizure freedom by early adulthood. In the long term, age at epilepsy onset has a crucial role in drug resistance and in developing intellectual disability, both in drug-resistant and drug-sensible patients. Patients with drug-refractory seizures tend to develop psychiatric issues, which should be recognized and adequately treated.
    Keywords:  TSC; adulthood; epilepsy; seizure; tuberous sclerosis complex
  2. Expert Rev Neurother. 2021 Mar 23.
      INTRODUCTION: Malformation of cortical development (MCD) is strongly associated with drug-resistant epilepsies for which surgery to remove epileptogenic lesions is common. Two notable technological advances in this field are identification of the underlying genetic cause and techniques in neuroimaging. These now question how pre-surgical evaluation ought to be approached for 'mTORpathies'.AREA COVERED: From review of published primary and secondary articles, the authors summarize evidence to consider focal cortical dysplasia (FCD), tuber sclerosis complex (TSC), and hemimegalencephaly (HME) collectively as MCD mTORpathies. The authors also consider the unique features of these related conditions with particular focus on the practicalities of using neuroimaging techniques currently available to define surgical targets and predict post-surgical outcome. Ultimately, the authors consider the surgical dilemmas faced for each condition.
    EXPERT OPINION: Considering FCD, TSC and HME collectively as mTORpathies has some merit; however, a unified approach to pre-surgical evaluation would seem unachievable. Nevertheless, the authors believe combining genetic-centered classification and morphologic findings using advanced imaging techniques will eventually form the basis of a paradigm when considering candidacy for early surgery.
    Keywords:  MRI; cortical development; developmental disorders; epilepsy; focal cortical dysplasia; hemimegalencephaly; mTORpathies; neuroimaging; tuberous sclerosis complex
  3. Front Immunol. 2021 ;12 637335
      Renal ischemia-reperfusion injury (IRI) contributes to acute kidney injury (AKI), increases morbidity and mortality, and is a significant risk factor for chronic kidney disease (CKD). Macrophage infiltration is a common feature after renal IRI, and infiltrating macrophages can be polarized into the following two distinct types: M1 macrophages, i.e., classically activated macrophages, which can not only inhibit infection but also accelerate renal injury, and M2 macrophages, i.e., alternatively activated macrophages, which have a repair phenotype that can promote wound healing and subsequent fibrosis. The role of TSC1, which is a negative regulator of mTOR signaling that regulates macrophage polarization in inflammation-linked diseases, has been well documented, but whether TSC1 contributes to macrophage polarization in the process of IRI is still unknown. Here, by using a mouse model of renal ischemia-reperfusion, we found that myeloid cell-specific TSC1 knockout mice (termed Lyz-TSC1 cKO mice) had higher serum creatinine levels, more severe histological damage, and greater proinflammatory cytokine production than wild-type (WT) mice during the early phase after renal ischemia-reperfusion. Furthermore, the Lyz-TSC1 cKO mice showed attenuated renal fibrosis during the repair phase of IRI with decreased levels of M2 markers on macrophages in the operated kidneys, which was further confirmed in a cell model of hypoxia-reoxygenation (H/R) in vitro. Mechanistically, by using RNA sequencing of sorted renal macrophages, we found that the expression of most M1-related genes was upregulated in the Lyz-TSC1 cKO group (Supplemental Table 1) during the early phase. However, C/EBPβ and CD206 expression was decreased during the repair phase compared to in the WT group. Overall, our findings demonstrate that the expression of TSC1 in macrophages contributes to the whole process of IRI but serves as an inflammation suppressor during the early phase and a fibrosis promoter during the repair phase.
    Keywords:  fibrosis; ischemia-reperfusion (IR); kidney; macrophage polarization; tuberous sclerosis complex 1 (TSC1)
  4. Semin Ophthalmol. 2021 Mar 23. 1-12
      BACKGROUND: Neurofibromatosis, Von Hippel Lindau disease, and tuberous sclerosis complex are classified under the term phakomatoses. They are characterized by ocular vascular abnormalities such as vascular tortuosity, corkscrew retinal vessel configuration, moyamoya-like aspect, microaneurysms, hemangioblastomas, and focal sheathing of retinal arteries, possibly due to abnormal formation, migration, and differentiation of neural crest cells. These alterations can be the first sign or the hallmark of disease and can be related to vasoproliferative tumors.PURPOSE: Novel imaging technologies in ophthalmology, such as near-infrared reflectances and spectral domain optical coherence tomography, have improved our knowledge in the diagnosis of these pathologies. Previously undetected macular vascular alterations have been reported in phakomatoses using optical coherence tomography angiography. This review will summarize the ophthalmic vascular abnormalities and novel imaging methods in the phakomatoses.
    CONCLUSION: Active research is being led into the ophthalmic management of these conditions and their complications, and owing to elevated vascular endothelial growth factor production from hemangioblastoma, hamartoma, and retinal vascular proliferative tumors, increasing interest in this line of therapy has been conducted although research is still ongoing in this area.
    Keywords:  Neurofibromatosis; Phakomatoses; Retinal-choroidal vascular abnormalities; Tuberous sclerosis complex; Von Hippel Lindau disease
  5. Jpn J Radiol. 2021 Mar 23.
      More than 10 hereditary renal tumor syndromes (HRTSs) and related germline mutations have been reported with HRTS-associated renal and extrarenal manifestations with benign and malignant tumors. Radiologists play an important role in detecting solitary or multiple renal masses with or without extrarenal findings on imaging and may raise the possibility of an inherited predisposition to renal cell carcinoma, providing direction for further screening, intervention and surveillance of the patients and their close family members before the development of potentially lethal renal and extrarenal tumors. Renal cell carcinomas (RCCs) associated with von Hippel-Lindau disease are typically slow growing while RCCs associated with HRTSs, such as hereditary leiomyomatosis and renal cell carcinoma syndrome, are highly aggressive. Therefore, radiologists need to be familiar with clinical and imaging findings of renal and extrarenal manifestations of HRTSs. This article reviews clinical and imaging findings for the evaluation of patients with well-established HRTSs from a radiologist's perspective to facilitate the clinical decision-making process for patient management.
    Keywords:  Birt–Hogg–Dubé syndrome; Hereditary leiomyomatosis and renal cell carcinoma syndrome; Hereditary renal tumor syndrome; Tuberous sclerosis complex; Von Hippel–Lindau disease
  6. CNS Drugs. 2021 Mar 22.
      BACKGROUND: Cannabidiol (CBD), which is one major constituent of the Cannabis sativa plant, has anti-seizure properties and does not produce euphoric or intrusive side effects. A plant-derived, highly purified CBD formulation with a known and constant composition has been approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. In the European Union, the drug has been authorized by the European Medicines Agency for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome, in conjunction with clobazam, and is under regulatory review for the treatment of seizures in patients with tuberous sclerosis complex.OBJECTIVES: This systematic review aimed to summarize the currently available body of knowledge about the use of this US Food and Drug Administration/European Medicines Agency-approved oral formulation of pharmaceutical-grade CBD in patients with epileptic conditions, especially developmental and epileptic encephalopathies other than Dravet syndrome and Lennox-Gastaut syndrome.
    METHODS: The relevant studies were identified through MEDLINE and the US National Institutes of Health Clinical Trials Registry in October 2020. There were no date limitations or language restrictions. The following types of studies were included: clinical trials, cohorts, case-control, cross-sectional, clinical series, and case reports. Participants had to meet the following criteria: any sex, any ethnicity, any age, diagnosis of epilepsy, receiving plant-derived, highly purified (> 98% w/w) CBD in a sesame oil-based oral solution for the treatment of seizures. Data extracted from selected records included efficacy, tolerability, and safety outcomes.
    RESULTS: Five hundred and seventy records were identified by database and trial register searching. Fifty-seven studies were retrieved for detailed assessment, of which 42 were eventually included for the review. The participants of the studies included patients of both pediatric and adult age. Across the trials, purified CBD was administered at dosages up to 50 mg/kg/day. In a randomized double-blind controlled trial in patients with tuberous sclerosis complex, CBD was associated with a significantly greater percent reduction in seizure frequency than placebo over the treatment period. Open-label studies suggested the effectiveness of CBD in the treatment of children and adults presenting with other epilepsy syndromes than those addressed by regulatory trials, including CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes, SYNGAP1 encephalopathy, and epilepsy with myoclonic absences. The most common adverse events observed during treatment with CBD included somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.
    CONCLUSIONS: The currently available data suggest that response to treatment with a highly purified, plant-derived CBD oil-based solution can be seen in patients across a broad range of epilepsy disorders and etiologies. The existing evidence can provide preliminary support for additional research.
  7. Acta Dermatovenerol Alp Pannonica Adriat. 2021 Mar;30(1): 35-37
      Periungual and subungual fibromas, also known as Koenen tumors, are diagnostic findings of tuberous sclerosis. The clinical appearance and histological features that characterize ungual fibromas are well defined. However, dermoscopic findings of these benign tumors have not been reported previously. Here we report a rare presentation of multiple subungual fibromas of all fingers in a developmentally delayed patient with tuberous sclerosis along with the dermoscopic features of the ungual tumors.
  8. Am J Med Genet A. 2021 Mar 22.
      Hemimegalencephaly (HME) is a rare hamartomatous congenital malformation of the brain characterized by dysplastic overgrowth of either one of the cerebral hemispheres. HME is associated with early onset seizures, abnormal neurological findings, and with subsequent cognitive and behavioral disabilities. Seizures associated with HME are often refractory to antiepileptic medications. Hemispherectomy is usually necessary to provide effective seizure control. The exact etiology of HME is not fully understood, but involves a disturbance in early brain development and likely involves genes responsible for patterning and symmetry of the brain. We present a female newborn who had refractory seizures due to HME. Whole genome sequencing revealed a novel, likely pathogenic, maternally inherited, 3Kb deletion encompassing exon 5 of the NPRL3 gene (chr16:161898-164745x1). The NPRL3 gene encodes for a nitrogen permease regulator 3-like protein, a subunit of the GATOR complex, which regulates the mTOR signaling pathway. A trial of mTOR inhibitor drug, Sirolimus, did not improve her seizure control. Functional hemispherectomy at 3 months of age resulted in total abatement of clinical seizures.
    Keywords:  NPRL3 gene; NPRL3 gene variant; hemimegalencephaly; infantile epilepsy; infantile epileptic encepahlopathy; intractable neonatal seizures
  9. Int Immunopharmacol. 2021 Mar 17. pii: S1567-5769(21)00188-0. [Epub ahead of print]95 107552
      Alveolar macrophages (AMs) are the lung resident macrophages critically involved in pulmonary homeostasis and immune response. Recent researches have uncovered a diversity of regulators responsible for the development, maintenance, and function of AMs. Nevertheless, the molecular underpinnings that determine the developmental and functional specification of AMs remain incompletely understood. Here, we investigated the role of the TSC1-mTOR pathway in murine AMs by genetic ablating Tsc1 or mTor alleles through Cd11c-Cre or LysM-Cre. Flow cytometry analyses revealed a prominent decrease in AMs in Tsc1f/f-Cd11c-Cre and Tsc1f/f/-LysM-Cre mice. Moreover, a reduction in AMs was also noted in mTorf/f-Cd11c-Cre or Rptorf/f-Cd11c-Cre mice. Further evidence implicated that elevation in cell death, most likely aberrant apoptosis or/and necroptosis, might be attributable to disrupted AM homeostasis. Whereas a diversity of cytokines involved in AM homeostasis and function triggered mTOR activation, only the IL-13 signaling, particularly Jak1 and Stat3 activation, was affected by TSC1 in macrophages. Further, select genes induced by IL-13, including AM surface markers such as Pparg, Fabp4/5, Nfil3 and Car4, and M2 hallmarks such as Arg1, Fizz, Ym1 and Clec7a were fine-tuned by the TSC1-mTOR pathway. Therefore, our results demonstrated that the TSC1-mTOR pathway has a crucial role in the homeostasis and functional specification of AMs through integrating cytokine signaling with metabolic cues.
    Keywords:  Alveolar macrophage; Apoptosis; IL-13; Necroptosis; TSC1; mTOR
  10. Physiol Rep. 2021 Mar;9(6): e14807
      The mechanistic target of rapamycin (mTOR) is a key mediator of energy metabolism, cell growth, and survival. While previous studies using transgenic mice with cardiac-specific overexpression of mTOR (mTOR-Tg) demonstrated the protective effects of cardiac mTOR against ischemia-reperfusion (I/R) injury in both ex vivo and in vivo models, the mechanisms underlying the role of cardiac mTOR in cardiac function following I/R injury are not well-understood. Torin1, a pharmacological inhibitor of mTOR complex (mTORC) 1 and mTORC2, significantly decreased functional recovery of LV developed pressure in ex vivo I/R models (p < 0.05). To confirm the role of mTOR complexes in I/R injury, we generated cardiac-specific mTOR-knockout (CKO) mice. In contrast to the effects of Torin1, CKO hearts recovered better after I/R injury than control hearts (p < 0.05). Interestingly, the CKO hearts had exhibited irregular contractions during the reperfusion phase. Calcium is a major factor in Excitation-Contraction (EC) coupling via Sarcoplasmic Reticulum (SR) calcium release. Calcium is also key in opening the mitochondrial permeability transition pore (mPTP) and cell death following I/R injury. Caffeine-induced SR calcium release in isolated CMs showed that total SR calcium content was lower in CKO than in control CMs. Western blotting showed that a significant amount of mTOR localizes to the SR/mitochondria and that GSK3-β phosphorylation, a key factor in SR calcium mobilization, was decreased. These findings suggest that cardiac mTOR located to the SR/mitochondria plays a vital role in EC coupling and cell survival in I/R injury.
    Keywords:  calcium; cardiomyocyte; ischemia-reperfusion; mTOR