bims-tubesc 2021-02-07 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2021–02–07
fiveteen papers selected by

Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin.
Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex.
Tuberous sclerosis complex: A multisystem disorder.
Finding new edges: systems approaches to MTOR signaling.
Neurite Outgrowth Inhibitor (NogoA) Is Upregulated in White Matter Lesions of Complex Cortical Malformations.
Tripartite suppression of fission yeast TORC1 signaling by the GATOR1-Sea3 complex, the TSC complex, and Gcn2 kinase.
Identification of TSC2 mosaic mutation limited to cortical tuber with TSC targeted sequencing: a case report and literature review.
Phosphatidic acid drives mTORC1 lysosomal translocation in the absence of amino acids.
Everolimus in adult tuberous sclerosis complex patients with epilepsy: Too late for success? A retrospective study.
Is Focal Cortical Dysplasia/Epilepsy Caused by Somatic MTOR Mutations Always a Unilateral Disorder?
Giant renal pseudoaneurysm complicating angiomyolipoma in a patient with tuberous sclerosis complex: An unusual case report and review of the literature.
Renal Neoplasia in Tuberous Sclerosis: A Study of 41 Patients.
Enhancing disease awareness for tuberous sclerosis complex in patients with radiologic diagnosis of renal angiomyolipoma: an observational study.
Early-Onset Developmental and Epileptic Encephalopathies of Infancy: An Overview of the Genetic Basis and Clinical Features.
mTOR inhibition: a double-edged sword in patients with COVID-19?

Sci Adv. 2021 Jan;pii: eabb1703. [Epub ahead of print]7(2):

Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin.

Pike-See Cheah, Shilpa Prabhakar, David Yellen, Roberta L Beauchamp, Xuan Zhang, Shingo Kasamatsu, Roderick T Bronson, Elizabeth A Thiele, David J Kwiatkowski, Anat Stemmer-Rachamimov, Bence György, King-Hwa Ling, Masao Kaneki, Bakhos A Tannous, Vijaya Ramesh, Casey A Maguire, Xandra O Breakefield.

Tuberous sclerosis complex (TSC) results from loss of a tumor suppressor gene - TSC1 or TSC2, encoding hamartin and tuberin, respectively. These proteins formed a complex to inhibit mTORC1-mediated cell growth and proliferation. Loss of either protein leads to overgrowth lesions in many vital organs. Gene therapy was evaluated in a mouse model of TSC2 using an adeno-associated virus (AAV) vector carrying the complementary for a "condensed" form of human tuberin (cTuberin). Functionality of cTuberin was verified in culture. A mouse model of TSC2 was generated by AAV-Cre recombinase disruption of Tsc2-floxed alleles at birth, leading to a shortened lifespan (mean 58 days) and brain pathology consistent with TSC. When these mice were injected intravenously on day 21 with AAV9-cTuberin, the mean survival was extended to 462 days with reduction in brain pathology. This demonstrates the potential of treating life-threatening TSC2 lesions with a single intravenous injection of AAV9-cTuberin.

DOI: https://doi.org/10.1126/sciadv.abb1703
Proc Natl Acad Sci U S A. 2021 Feb 09. pii: e2020190118. [Epub ahead of print]118(6):

Kidney intercalated cells and the transcription factor FOXi1 drive cystogenesis in tuberous sclerosis complex.

Sharon Barone, Kamyar Zahedi, Marybeth Brooks, Elizabeth P Henske, Yirong Yang, Erik Zhang, John J Bissler, Jane J Yu, Manoocher Soleimani.

  Tuberous sclerosis complex (TSC) is caused by mutations in either TSC1 or TSC2 genes and affects multiple organs, including kidney, lung, and brain. In the kidney, TSC presents with the enlargement of benign tumors (angiomyolipomata) and cysts, which eventually leads to kidney failure. The factors promoting cyst formation and tumor growth in TSC are incompletely understood. Here, we report that mice with principal cell-specific inactivation of Tsc1 develop numerous cortical cysts, which are overwhelmingly composed of hyperproliferating A-intercalated (A-IC) cells. RNA sequencing and confirmatory expression studies demonstrated robust expression of Forkhead Transcription Factor 1 (Foxi1) and its downstream targets, apical H+-ATPase and cytoplasmic carbonic anhydrase 2 (CAII), in cyst epithelia in Tsc1 knockout (KO) mice but not in Pkd1 mutant mice. In addition, the electrogenic 2Cl-/H+ exchanger (CLC-5) is significantly up-regulated and shows remarkable colocalization with H+-ATPase on the apical membrane of cyst epithelia in Tsc1 KO mice. Deletion of Foxi1, which is vital to intercalated cells viability and H+-ATPase expression, completely abrogated the cyst burden in Tsc1 KO mice, as indicated by MRI images and histological analysis in kidneys of Foxi1/Tsc1 double-knockout (dKO) mice. Deletion of CAII, which is critical to H+-ATPase activation, caused significant reduction in cyst burden and increased life expectancy in CAII/Tsc1 dKO mice vs. Tsc1 KO mice. We propose that intercalated cells and their acid/base/electrolyte transport machinery (H+-ATPase/CAII/CLC-5) are critical to cystogenesis, and their inhibition or inactivation is associated with significant protection against cyst generation and/or enlargement in TSC.

Keywords:  H+-ATPase; cortical collecting duct; cysts; intercalated cells; prorenin receptor

DOI:  https://doi.org/10.1073/pnas.2020190118
JAAPA. 2021 Feb 27.

Tuberous sclerosis complex: A multisystem disorder.

Kelliann Notaro, Bradley Pierce.

ABSTRACT: Tuberous sclerosis complex (TSC) is a genetic disorder that affects multiple organ systems but often goes unrecognized, and a delay in diagnosis can lead to multiple complications. Healthcare professionals should be educated on the many signs and symptoms associated with the disorder, know how to treat them symptomatically, and recommend routine screening to assess for complications. Correctly identifying, diagnosing, and treating TSC can give patients a better quality of life and prevent further complications associated with the disorder.

DOI: https://doi.org/10.1097/01.JAA.0000733220.26720.62
Biochem Soc Trans. 2021 Feb 05. pii: BST20190730. [Epub ahead of print]

Finding new edges: systems approaches to MTOR signaling.

Alexander Martin Heberle, Ulrike Rehbein, Maria Rodríguez Peiris, Kathrin Thedieck.

  Cells have evolved highly intertwined kinase networks to finely tune cellular homeostasis to the environment. The network converging on the mechanistic target of rapamycin (MTOR) kinase constitutes a central hub that integrates metabolic signals and adapts cellular metabolism and functions to nutritional changes and stress. Feedforward and feedback loops, crosstalks and a plethora of modulators finely balance MTOR-driven anabolic and catabolic processes. This complexity renders it difficult - if not impossible - to intuitively decipher signaling dynamics and network topology. Over the last two decades, systems approaches have emerged as powerful tools to simulate signaling network dynamics and responses. In this review, we discuss the contribution of systems studies to the discovery of novel edges and modulators in the MTOR network in healthy cells and in disease.

Keywords:  amino acids; computational models; mechanistic target of rapamycin; protein kinase B; signaling; systems biology

DOI:  https://doi.org/10.1042/BST20190730
J Neuropathol Exp Neurol. 2021 Jan 31. pii: nlaa159. [Epub ahead of print]

Neurite Outgrowth Inhibitor (NogoA) Is Upregulated in White Matter Lesions of Complex Cortical Malformations.

Theresa Scholl, Victoria-Elisabeth Gruber, Sharon Samueli, Reinhard Lehner, Gregor Kasprian, Thomas Czech, Roy J Reinten, Lisette Hoogendijk, Johannes A Hainfellner, Eleonora Aronica, Angelika Mühlebner, Martha Feucht.

  Complex cortical malformations (CCMs), such as hemimegalencephaly and polymicrogyria, are associated with drug-resistant epilepsy and developmental impairment. They share certain neuropathological characteristics including mammalian target of rapamycin (mTOR) activation and an atypical number of white matter neurons. To get a better understanding of the pathobiology of the lesion architecture, we investigated the role of neurite outgrowth inhibitor A (NogoA), a known regulator of neuronal migration. Epilepsy surgery specimens from 16 CCM patients were analyzed and compared with sections of focal cortical dysplasia IIB (FCD IIB, n = 22), tuberous sclerosis complex (TSC, n = 8) as well as healthy controls (n = 15). Immunohistochemistry was used to characterize NogoA, myelination, and mTOR signaling. Digital slides were evaluated automatically with ImageJ. NogoA staining showed a significantly higher expression within the white matter of CCM and FCD IIB, whereas cortical tubers presented levels similar to controls. Further analysis of possible associations of NogoA with other factors revealed a positive correlation with mTOR and seizure frequency. To identify the main expressing NogoA cell type, double staining revealed dysmorphic neuronal white matter cells. Increased NogoA expression is associated with profound inhibition of neuritic sprouting and therefore contributes to a decrease in neuronal network complexity in CCM patients.

Keywords:  Epilepsy surgery; Hemimegalencephaly; Polymicrogyria; White matter pathology

DOI:  https://doi.org/10.1093/jnen/nlaa159
Elife. 2021 Feb 03. pii: e60969. [Epub ahead of print]10

Tripartite suppression of fission yeast TORC1 signaling by the GATOR1-Sea3 complex, the TSC complex, and Gcn2 kinase.

Tomoyuki Fukuda, Fajar Sofyantoro, Yen Teng Tai, Kim Hou Chia, Takato Matsuda, Takaaki Murase, Yuichi Morozumi, Hisashi Tatebe, Tomotake Kanki, Kazuhiro Shiozaki.

  Mammalian target of rapamycin complex 1 (TORC1) is controlled by the GATOR complex composed of the GATOR1 subcomplex and its inhibitor, the GATOR2 subcomplex, sensitive to amino acid starvation. Previously, we identified fission yeast GATOR1 that prevents deregulated activation of TORC1 (Chia et al., 2017). Here, we report identification and characterization of GATOR2 in fission yeast. Unexpectedly, the GATOR2 subunit Sea3, an ortholog of mammalian WDR59, is physically and functionally proximal to GATOR1, rather than GATOR2, attenuating TORC1 activity. The fission yeast GATOR complex is dispensable for TORC1 regulation in response to amino acid starvation, which instead activates the Gcn2 pathway to inhibit TORC1 and induce autophagy. On the other hand, nitrogen starvation suppresses TORC1 through the combined actions of the GATOR1-Sea3 complex, the Gcn2 pathway, and the TSC complex, another conserved TORC1 inhibitor. Thus, multiple, parallel signaling pathways implement negative regulation of TORC1 to ensure proper cellular starvation responses.

Keywords:  Autophagy; GATOR1; GATOR2; Gcn2; Rag GTPase; S. pombe; TORC1; cell biology

DOI:  https://doi.org/10.7554/eLife.60969
Childs Nerv Syst. 2021 Jan 30.

Identification of TSC2 mosaic mutation limited to cortical tuber with TSC targeted sequencing: a case report and literature review.

Yuanfeng Zhou, Xinhua Wang, Ji Wang, Yifeng Ding, Yi Wang, Hao Li, Rui Zhao, Bingbing Wu.

   BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder, mainly in childhood presents epilepsy due to cortical tubers. TSC1/TSC2 pathogenic variants cannot be detected in regular molecular genetic testing in around 10-15% of TSC patients.
METHODS: We analyzed TSC genes in both cortical tuber, blood and skin samples from a pediatric patient with refractory epilepsy.
RESULTS: We found no germline mutations by whole-exome sequencing. Well in targeted sequencing of TSC1/2 data, we identified de novo mutations only in cortical tuber: TSC2 NM_000548.5: exon34:c.4183C>T (p.Gln1395*) in 3% of the alleles. No other TSC mutations were found in patient's blood and skin samples and her parents' blood sample.
CONCLUSION: Our case report found TSC2 mosaic mutations can be only limited to cortical tuber in patients with TSC.

Keywords:  Cortical tuber; TSC2; Targeted sequencing; Tuberous sclerosis complex

DOI:  https://doi.org/10.1007/s00381-021-05059-1
J Biol Chem. 2020 Jan 03. pii: S0021-9258(17)49565-2. [Epub ahead of print]295(1): 263-274

Phosphatidic acid drives mTORC1 lysosomal translocation in the absence of amino acids.

Maria A Frias, Suman Mukhopadhyay, Elyssa Lehman, Aleksandra Walasek, Matthew Utter, Deepak Menon, David A Foster.

  Mammalian target of rapamycin complex 1 (mTORC1) promotes cell growth and proliferation in response to nutrients and growth factors. Amino acids induce lysosomal translocation of mTORC1 via the Rag GTPases. Growth factors activate Ras homolog enriched in brain (Rheb), which in turn activates mTORC1 at the lysosome. Amino acids and growth factors also induce the phospholipase D (PLD)-phosphatidic acid (PA) pathway, required for mTORC1 signaling through mechanisms that are not fully understood. Here, using human and murine cell lines, along with immunofluorescence, confocal microscopy, endocytosis, PLD activity, and cell viability assays, we show that exogenously supplied PA vesicles deliver mTORC1 to the lysosome in the absence of amino acids, Rag GTPases, growth factors, and Rheb. Of note, pharmacological or genetic inhibition of endogenous PLD prevented mTORC1 lysosomal translocation. We observed that precancerous cells with constitutive Rheb activation through loss of tuberous sclerosis complex subunit 2 (TSC2) exploit the PLD-PA pathway and thereby sustain mTORC1 activation at the lysosome in the absence of amino acids. Our findings indicate that sequential inputs from amino acids and growth factors trigger PA production required for mTORC1 translocation and activation at the lysosome.

Keywords:  amino acid; cancer biology; cancer therapy; growth factor; lysosome; mTOR complex (mTORC); phosphatidic acid; phospholipase D; phospholipid vesicle

DOI:  https://doi.org/10.1074/jbc.RA119.010892
Epilepsia. 2021 Feb 03.

Everolimus in adult tuberous sclerosis complex patients with epilepsy: Too late for success? A retrospective study.

Jakob Stockinger, Adam Strzelczyk, Andrea Nemecek, Michal Cicanic, Frank Bösebeck, Christian Brandt, Hajo Hamer, Tassanai Intravooth, Bernhard J Steinhoff.

   OBJECTIVE: There is evidence that everolimus (EVE) significantly reduces seizure frequency in epilepsy patients with tuberous sclerosis complex (TSC). Given that TSC-related proliferative processes are more dynamic during brain development, seizure outcomes of patients treated with EVE may be age-related and may be less convincing in adult patients. The aim of this study was to assess the effectiveness and the safety profile of EVE in adults in clinical practice.
METHODS: We performed a multicenter retrospective chart review of TSC subjects with active epilepsy who started EVE in adulthood (≥18 years of age) at seven German epilepsy centers. The primary endpoint was the retention rate after 6 months.
RESULTS: A total of 45 subjects with a mean age of 31.6 ± 11.1 years at EVE start fulfilled the inclusion criteria. Retention rate after 6 months was 98% (43/44 evaluable subjects). Response rate (seizure reduction ≥ 50%) was 33% (14/43 evaluable subjects; four completely seizure-free). We did not find a significant relationship between epilepsy outcome parameters and patient age at EVE start. Adverse events were reported in 19 subjects and were judged to be serious in six patients. Three patients died during the observation period.
SIGNIFICANCE: Evidence suggests that EVE is an effective add-on treatment for epilepsy in adult TSC patients, surprisingly without any age limit to individual benefit. A strong age-dependent effect within the period of adulthood seems unlikely. Even if there was no proof of a causal relationship between deaths and EVE intake, patients with EVE should be carefully monitored, especially for infections and stomatitis.

Keywords:  disease-modifying therapy; epilepsy; everolimus; tuberous sclerosis complex

DOI:  https://doi.org/10.1111/epi.16829
Neurol Genet. 2021 Feb;7(1): e540

Is Focal Cortical Dysplasia/Epilepsy Caused by Somatic MTOR Mutations Always a Unilateral Disorder?

Renzo Guerrini, Mara Cavallin, Tommaso Pippucci, Anna Rosati, Francesca Bisulli, Paola Dimartino, Carmen Barba, Rita Garbelli, Anna Maria Buccoliero, Laura Tassi, Valerio Conti.

Objective: To alert about the wide margin of unpredictability that distribution of somatic MTOR mosaicism may have in the brain and the risk for independent epileptogenesis arising from the seemingly healthy contralateral hemisphere after complete removal of epileptogenic focal cortical dysplasia (FCD).
Methods: Clinical, EEG, MRI, histopathology, and molecular genetics in 2 patients (1 and 2) treated with focal resections and subsequent complete hemispherectomy for epileptogenic FCD due to somatic MTOR mutations. Autoptic brain study of bilateral asymmetric hemispheric dysplasia and identification of alternative allele fraction (AAF) rates for AKT1 (patient 3).
Results: The strongly hyperactivating p.Ser2215Phe (patient 1) and p.Leu1460Pro (patient 2) MTOR mutations were at low-level AAF in the dysplastic tissue. After repeated resections and eventual complete hemispherectomy, both patients manifested intractable seizures arising from the contralateral, seemingly healthy hemisphere. In patient 3, the p.Glu17Lys AKT1 mutation exhibited random distribution and AAF rates in different tissues with double levels in the more severely dysplastic cerebral hemisphere.
Conclusions: Our understanding of the distribution of somatic mutations in the brain in relation to the type of malformation and its hypothesized time of origin may be faulty. Large studies may reveal that the risk of a first surgery being disappointing might be related more to the specific somatic mammalian target of rapamycin mutation identified than to completeness of resection and that the advantages of repeated resections after a first unsuccessful operation should be weighed against the risk of the contralateral hemisphere becoming in turn epileptogenic.

DOI: https://doi.org/10.1212/NXG.0000000000000540
Ann Med Surg (Lond). 2021 Feb;62 131-134

Giant renal pseudoaneurysm complicating angiomyolipoma in a patient with tuberous sclerosis complex: An unusual case report and review of the literature.

Habib Ahmad Esmat, Mohammad Wali Naseri.

   Introduction: Angiomyolipomas (AMLs) are uncommon benign lesions, which are composed of dysmorphic blood vessels, adipose tissue, and smooth muscle components. They tend to bleed because of the hypervascularity and the presence of small aneurysms, leading to life-threatening complications.
Presentation of case: A 31-year-old female was presented to the emergency service of our hospital, complaining of left flank pain for 1 week followed by hematuria for one day. Radiologic imaging showed the features of a giant renal pseudoaneurysm. Superselective embolization was applied and she had an uneventful recovery.
Discussion: The blood vessels in AML are tortuous and thick-walled with the absence of supportive elastic tissue, which tend to the formation of the intralesional pseudoaneurysm. The risk of bleeding is higher with tumors larger than 4 cm, rapid tumor growth, and aneurysms larger than 0.5 cm. Early detection and treatment are essential for the prevention of bleeding and improving patient outcomes.
Conclusion: Giant pseudoaneurysm in a renal angiomyolipoma associated with tuberous sclerosis complex is a rare entity, often leading to potentially life-threatening bleeding. Selective angioembolization is recommended as firstline therapy for bleeding AML and is increasingly used as a preventive treatment for AML at risk of bleeding. However, a high incidence of the recurrence requires caution and a close longtime follow-up. Surgical intervention is indicated if the hemorrhage is not responsive to embolization or if there is suspicion of malignancy.

Keywords:  AMLs, Angiomyolipomas; Angiomyolipoma; Case report; Renal pseudoaneurysm; TSC, Tuberous sclerosis complex; Tuberous sclerosis

DOI:  https://doi.org/10.1016/j.amsu.2021.01.014
Mayo Clin Proc. 2021 Jan 29. pii: S0025-6196(20)31313-6. [Epub ahead of print]

Renal Neoplasia in Tuberous Sclerosis: A Study of 41 Patients.

Sounak Gupta, Rafael E Jimenez, Loren Herrera-Hernandez, Christine M Lohse, R Houston Thompson, Stephen A Boorjian, Bradley C Leibovich, John C Cheville.

OBJECTIVE: To study the clinical features and identify unique renal neoplasia subtypes and their prognostic implications in individuals with tuberous sclerosis complex (TSC).
PATIENTS AND METHODS: The Mayo Clinic nephrectomy registry included 37 patients with TSC diagnosed between 1970 and 2018. Four additional patients were identified from the pathology consultation and autopsy files. All available renal tumors were further characterized using immunohistochemistry and fluorescence in situ hybridization. Clinicopathologic features and follow-up were obtained from the medical record. The American Association for Cancer Research Project GENIE registry was accessed using cBioPortal for molecular profiling of angiomyolipoma (AML).
RESULTS: A total of 276 renal tumors from 41 patients were analyzed. Renal tumors were classified into 9 distinct morphological subtypes, with AML predominating (238 [86%]). Interestingly, all these tumors acted in a benign fashion except one renal cell carcinoma with clear cells and fibromyomatous stroma and one epithelioid AML that metastasized. Molecular profiling studies revealed that epithelioid AMLs were enriched for alterations of TP53, RB1, and ATRX. Eight patients died of direct complications of TSC, including 3 of end-stage renal disease. To date, none have died of a renal epithelial neoplasm.
CONCLUSION: The identification of unique renal neoplasia subtypes may provide important clues to establish a diagnosis of TSC, and in the somatic setting, this finding has important implications for accurate prognostication. These tumors tend to be indolent, and only 2 of 276 tumors in our study exhibited metastatic behavior. Our results support multidisciplinary management with a focus on preservation of renal function.

DOI: https://doi.org/10.1016/j.mayocp.2020.11.004
BMC Nephrol. 2021 Jan 31. 22(1): 47

Enhancing disease awareness for tuberous sclerosis complex in patients with radiologic diagnosis of renal angiomyolipoma: an observational study.

Kathrin Bausch, Christian Wetterauer, Julian Diethelm, Jan Ebbing, Daniel T Boll, Patricia Dill, Cyrill A Rentsch, Hans-H Seifert.

   BACKGROUND: Tuberous Sclerosis Complex (TSC) is a genetic disorder, with renal manifestations like angiomyolipoma (AML) occurring in 70-80% of patients. AML usually cause more complications in TCS patients than in non-TSC patients. However, AML patients are not routinely investigated for TSC. Our aim was to retrospectively assess the correlation between radiologically diagnosed AML and TSC.
METHODS: All patients were stratified into AML related vs. unrelated to TSC. Correlations were calculated to determine the association between age, AML, and TSC.
RESULTS: Complete data were available for 521 patients with renal AML, in 7 of which the concurrent diagnosis of TSC was found. Younger age significantly positively correlated with the prevalence of TSC in AML patients (p < 0.01). 37 (7%) of the 521 patients were within the age-range of 18-40 years, in which TSC occurred in 6 cases, 4 (66.7%) of which presented with multiple, bilateral renal AML (p < 0.05), and 2 (33.3%) of which with a single, unilateral AML (p < 0.05). In patients with AML but without TSC, unilateral AML was found in 83.9% and bilateral AML in 16.1% (p < 0.05). Simple binary logistic regression analysis revealed bilateral AML (OR 33.0; 95% CI 3.2-344.0; p = 0.003) (but not unilateral AML (OR 0.09; 95% CI 0.01-0.88; p = 0.04)) to be a risk factor for TSC.
CONCLUSIONS: The presence of bilateral AML in patients within the age-range of 18-40 years should raise suspicion for TSC as the underlying cause. Therefore, our advice is to refer patients with multiple bilateral renal AML for further investigations regarding TSC.

Keywords:  Angiomyolipoma; Chronic kidney disease; Renal angiomyolipoma; Tuberous sclerosis; Tuberous sclerosis complex

DOI:  https://doi.org/10.1186/s12882-021-02253-w
Pediatr Neurol. 2020 Dec 13. pii: S0887-8994(20)30386-6. [Epub ahead of print]116 85-94

Early-Onset Developmental and Epileptic Encephalopathies of Infancy: An Overview of the Genetic Basis and Clinical Features.

Nadine Morrison-Levy, Felippe Borlot, Puneet Jain, Robyn Whitney.

  Our current knowledge of genetically determined forms of epilepsy has shortened the diagnostic pathway usually experienced by the families of infants diagnosed with early-onset developmental and epileptic encephalopathies. Genetic causes can be found in up to 80% of infants presenting with early-onset developmental and epileptic encephalopathies, often in the context of an uneventful perinatal history and with no clear underlying brain abnormalities. Although current disease-specific therapies remain limited and patient outcomes are often guarded, a genetic diagnosis may lead to early therapeutic intervention using new and/or repurposed therapies. In this review, an overview of epilepsy genetics, the indications for genetic testing in infants, the advantages and limitations of each test, and the challenges and ethical implications of genetic testing are discussed. In addition, the following causative genes associated with early-onset developmental and epileptic encephalopathies are discussed in detail: KCNT1, KCNQ2, KCNA2, SCN2A, SCN8A, STXBP1, CDKL5, PIGA, SPTAN1, and GNAO1. The epilepsy phenotypes, comorbidities, electroencephalgraphic findings, neuroimaging findings, and potential targeted therapies for each gene are reviewed.

Keywords:  Developmental and epileptic encephalopathies; Early-onset epileptic encephalopathy; Epilepsy genetics; Infants; Precision medicine

DOI:  https://doi.org/10.1016/j.pediatrneurol.2020.12.001
Hum Cell. 2021 Feb 01.

mTOR inhibition: a double-edged sword in patients with COVID-19?

Morteza Ghasemnejad-Berenji.

  The current COVID-19 is one of the deadliest pandemics in recent decades. In the lack of a specific treatment for this novel infection, knowing the role of cell signaling pathways in the pathogenesis of this infection could be useful in finding effective drugs against this disease. The mammalian or mechanistic target of rapamycin (mTOR) is an important cell signaling pathway that has important role in the regulation of cell growth, protein synthesis, and metabolism in reactance to upstream signals in both pathological and normal physiological conditions. Recently, some researchers have suggested the therapeutic potential of mTOR inhibitors such as rapamycin against COVID-19. However, it is important to consider the role of activation of this pathway in controlling immune system response against viral activity in drug repositioning of rapamycin and other mTOR inhibitors in SARS-CoV-2 infection.

Keywords:  COVID-19; Cell signaling; Immune system; Rapamycin; SARS-CoV-2; mTOR

DOI:  https://doi.org/10.1007/s13577-021-00495-2