Neurology, Neuropsychiatry, Psychosomatics

Advanced search

COVID 19 in a family with rare genetic disease of the nervous system

Full Text:


We present familial tuberous sclerosis (TS) case complicated by COVID-19. COVID-19 aggravates the course of TS and may lead to a fatal outcome. We review the role of mTORC1 (mechanistic/mammalian Target of Rapamycin Complex 1) in the development and functions of the nervous system and the pathogenesis of TS and COVID-19 with emphasis on the involvement of the brain and lungs. We observed that COVID-19 worsens the course of epilepsy in patients with TS. In TS patients, lymphangioleiomyomatosis may predispose to SARS-CoV-2 invasion into the respiratory system because of the increased expression of ACE2 and TMPRSS2 in type II pneumocytes and thus may worsen the prognosis. We also review the current data on the continuation/termination of everolimus administration in patients with TS associated with COVID-19. 

About the Authors

M. Yu. Martynov
N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia; Federal Center of Brain and Neurotechnologies, FMBA of Russia
Russian Federation

1, Ostrovityanov St., Moscow 117997;

1, Ostrovityanov St., Build 10, Moscow 117513

V. A. Kutashov
N.N. Burdenko Voronezh State Medical University, Ministry of Health of Russia
Russian Federation

10, Studencheskaya St., Voronezh 394036

O. V. Ulyanova
N.N. Burdenko Voronezh State Medical University, Ministry of Health of Russia
Russian Federation

10, Studencheskaya St., Voronezh 394036


1. Le Bert N, Clapham HE, Tan AT, et al. Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV2 infection. J Exp Med. 2021;218(5):e20202617. doi: 10.1084/jem.20202617

2. Izcovich A, Ragusa MA, Tortosa F, et al. Prognostic factors for severity and mortality in patients infected with COVID-19: A systematic review. PLoS One. 2020 Nov 17;15(11):e0241955. doi: 10.1371/journal.pone.0241955. eCollection 2020.

3. Malle L, Gao C, Hur C, et al. Individuals with Down syndrome hospitalized with COVID-19 have more severe disease. Genet Med. 2021 Mar;23(3):576-80. doi: 10.1038/s41436-020-01004-w. Epub 2020 Oct 16.

4. Araya P, Waugh KA, Sullivan KD, et al. Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity. Proc Natl Acad Sci U S A. 2019 Nov 26;116(48):24231-41. doi: 10.1073/pnas.1908129116. Epub 2019 Nov 7.

5. Dieudonne Y, Uring-Lambert B, Jeljeli MM, et al. Immune defect in adults with Down syndrome: insights into a complex issue. Front Immunol. 2020 May 8;11:840. doi: 10.3389/fimmu.2020.00840.eCollection 2020.

6. Fierro L, Nesheiwat N, Naik H, et al. Gaucher disease and SARS-CoV-2 infection: Experience from 181 patients in New York. Mol Genet Metab. 2021 Jan;132(1):44-8. doi: 10.1016/j.ymgme.2020.12.288. Epub 2020 Dec 15.

7. Henske EP, Jozwiak S, Kingswood JC, et al. Tuberous sclerosis complex. Nat Rev Dis Primers. 2016 May 26;2:16035. doi: 10.1038/nrdp.2016.35

8. Dorofeeva MYu, Belousova ED, Pivovarova AM, et al. The first results of tuberous sclerosis registry. Rossiyskiy vestnik perinatologii i pediatrii = Russian Bulletin of Perinatology and Pediatrics. 2015;60(5):113-20 (In Russ.).

9. Tee AR, Fingar DC, Manning BD, et al. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13571-6. doi: 10.1073/pnas.202476899. Epub 2002 Sep 23.

10. Dabora SL, Jozwiak S, Franz DN, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet. 2001 Jan;68(1):64-80. doi: 10.1086/316951. Epub 2000 Dec 8.

11. Dufner Almeida LG, Nanhoe S, Zonta A, et al. Comparison of the functional and structural characteristics of rare TSC2 variants with clinical and genetic findings. Hum Mutat. 2020 Apr;41(4):759-73. doi: 10.1002/humu.23963. Epub 2019 Dec 19.

12. Parkhitko AA, Favorova OO, Khabibullin DI, et al. Kinase mTOR: regulation and role in maintenance of cellular homeostasis, tumor development and aging. Biochemistry (Moscow). 2014;79(2):128-43 (In Russ.).

13. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017 Mar 9;168(6):960-76. doi: 10.1016/j.cell.2017.02.004

14. Katholnig K, Linke M, Pham H, et al. Immune responses of macrophages and dendritic cells regulated by mTOR signalling. Biochem Soc Trans. 2013 Aug;41(4):927-33. doi: 10.1042/BST20130032

15. Linke M, Fritsch SD, Sukhbaatar N, et al. mTORC1 and mTORC2 as regulators of cell metabolism in immunity. FEBS Lett. 2017 Oct;591(19):3089-103. doi: 10.1002/1873-3468.12711. Epub 2017 Jun 23.

16. Fekete T, Agics B, Bencze D, et al. Regulation of RLR-mediated antiviral responses of human dendritic cells by mTOR. Front Immunol. 2020 Sep 11;11:572960. doi: 10.3389/fimmu.2020.572960. eCollection 2020.

17. Le Sage V, Cinti A, Amorim R, Mouland AJ. Adapting the stress response: viral subversion of the mTOR signaling pathway. Viruses. 2016 May 24;8(6):152. doi: 10.3390/v8060152

18. Oh SJ, Shin OS. SARS-CoV-2 nucleocapsid protein targets RIG-I-like receptor pathways to inhibit the induction of interferon response. Cells. 2021 Mar 2;10(3):530. doi: 10.3390/cells10030530

19. Wang W, Zhou Z, Xiao X, et al. SARS-CoV-2 NSP12 attenuates type I interferon production by inhibiting IRF3 nuclear translocation. Cell Mol Immunol. 2021 Apr;18(4):945-53. doi: 10.1038/s41423-020-00619-y. Epub 2021 Feb 26.

20. Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013 Jan 12;381(9861):125-32. doi: 10.1016/S0140- 6736(12)61134-9. Epub 2012 Nov 14.

21. Bissler JJ, Kingswood JC, Radzikowska E, et al. Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial. Nephrol Dial Transplant. 2016;31(1):111-9. doi: 10.1093/ndt/gfv249

22. Li M, Zhou Y, Chen C, et al. Efficacy and safety of mTOR inhibitors (rapamycin and its analogues) for tuberous sclerosis complex: a meta-analysis. Orphanet J Rare Dis. 2019 Feb 13;14(1):39. doi: 10.1186/s13023-019-1012-x

23. Willems LM, Rosenow F, Schubert-Bast S, et al. Efficacy, retention and tolerability of Everolimus in patients with Tuberous Sclerosis Complex: a survey-based study on patients' perspectives. CNS Drugs. 2021 Oct;35(10):1107-22. doi: 10.1007/s40263-021-00839-4. Epub 2021 Jul 17.

24. Johnson SR, Taveira-DaSilva AM, Moss J. Lymphangioleiomyomatosis. Clin Chest Med. 2016 Sep;37(3):389-403. doi: 10.1016/j.ccm.2016.04.002

25. Kingswood JC, Belousova E, Benedik MP, et al. Renal manifestations of Tuberous Sclerosis Complex: key findings from the final analysis of the TOSCA study focusing mainly on renal angiomyolipomas. Front Neurol. 2020 Sep 16;11:972. doi: 10.3389/fneur.2020.00972. eCollection 2020.

26. Peron A, La Briola F, Bruschi F, et al. Tuberous sclerosis complex (TSC), lymphangioleiomyomatosis, and COVID-19: The experience of a TSC clinic in Italy. Am J Med Genet A. 2020 Nov;182(11):2479-85. doi: 10.1002/ajmg.a.61810. Epub 2020 Aug 17.

27. Tang Y, Kwiatkowski DJ, Henske EP. mTORC1 hyperactivation in lymphangioleiomyomatosis leads to ACE2 upregulation in type II pneumocytes: implications for COVID-19. Eur Respir J. 2021 Feb 11;57(2):2002737. doi: 10.1183/13993003.02737-2020. Print 2021 Feb.

28. Shi G, Chiramel AI, Majdoul S, et al. Rapalogs down modulate intrinsic immunity and promote cell entry of SARS-CoV-2. bioRxiv [Preprint]. 2021:2021.04.15.440067. doi: 10.1101/2021.04.15.440067

29. Lesma E, Ancona S, Sirchia SM, et al. TSC2 epigenetic defect in primary LAM cells. Evidence of an anchorage-independent survival. J Cell Mol Med. 2014 May;18(5):766-79. doi: 10.1111/jcmm.12237. Epub 2014 Mar 7.

30. Bockaert J, Marin P. mTOR in brain physiology and pathologies. Physiol Rev. 2015 Oct;95(4):1157-87. doi: 10.1152/physrev.00038.2014

31. Grabole N, Zhang JD, Aigner S, et al. Genomic analysis of the molecular neuropathology of tuberous sclerosis using a human stem cell model. Genome Med. 2016 Sep 21;8(1):94. doi: 10.1186/s13073-016- 0347-3

32. Martin KR, Zhou W, Bowman MJ, et al. The genomic landscape of tuberous sclerosis complex. Nat Commun. 2017 Jun 15;8:15816. doi: 10.1038/ncomms15816

33. Zhang B, Zou J, Rensing NR, et al. Inflammatory mechanisms contribute to the neurological manifestations of tuberous sclerosis complex. Neurobiol Dis. 2015 Aug;80:70-9. doi: 10.1016/j.nbd.2015.04.016. Epub 2015 May 21.

34. Chen R, Wang K, Yu J, et al. The Spatial and Cell-Type Distribution of SARS-CoV-2 Receptor ACE2 in the Human and Mouse Brains. Front Neurol. 2021 Jan 20;11:573095. doi: 10.3389/fneur.2020.573095. eCollection 2020.

35. Cosentino G, Todisco M, Hota N, et al. Neuropathological findings from COVID-19 patients with neurological symptoms argue against a direct brain invasion of SARS-CoV-2: a critical systematic review. Eur J Neurol. 2021 Nov;28(11):3856-65. doi: 10.1111/ene.15045. Epub 2021 Aug 17.

36. Dorofeeva MYu, Belousova ED. Features of the course and treatment of epilepsy in children with tuberous sclerosis. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova = S.S. Korsakov Journal of Neurology and Psychiatry. 2012;112(6-2):27-31 (In Russ.).

37. Zeng LH, Rensing NR, Zhang B, et al. TSC 2 gene inactivation causes a more severe epilepsy phenotype than TSC 1 inactivation in a mouse model of tuberous sclerosis complex. Hum Mol Genet. 2011 Feb 1;20(3):445-54. doi: 10.1093/hmg/ddq491. Epub 2010 Nov 9.

38. Au KS, Williams AT, Roach ES, et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med. 2007 Feb;9(2):88-100. doi: 10.1097/gim.0b013e31803068c7

39. Sun M, Ruan X, Li Y, et al. Clinical characteristics of 30 COVID-19 patients with epilepsy: A retrospective study in Wuhan. Int J Infect Dis. 2021 Feb;103:647-53. doi: 10.1016/j.ijid.2020.09.1475. Epub 2020 Oct 2.

40. Kaur S, Lal L, Sassano A, et al. Regulatory effects of mammalian target of rapamycin-activated pathways in type I and II interferon signaling. J Biol Chem. 2007 Jan 19;282(3):1757-68. doi: 10.1074/jbc.M607365200. Epub 2006 Nov 17.

41. Shi G, Ozog S, Torbett BE, Compton AA. mTOR inhibitors lower an intrinsic barrier to virus infection mediated by IFITM3. Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):E10069-E10078. doi: 10.1073/pnas.1811892115. Epub 2018 Oct 9.

42. Mercalli A, Calavita I, Dugnani E, et al. Rapamycin unbalances the polarization of human macrophages to M1. Immunology. 2013 Oct;140(2):179-90. doi: 10.1111/imm.12126

43. Baker AK, Wang R, Mackman N, Luyendyk JP. Rapamycin enhances LPS induction of tissue factor and tumor necrosis factor-alpha expression in macrophages by reducing IL-10 expression. Mol Immunol. 2009 Jul;46(11-12):2249-55. doi: 10.1016/j.molimm.2009.04.011. Epub 2009 May 17.

44. Zhou R, To KK, Wong YC, et al. Acute SARS-CoV-2 infection impairs dendritic cell and T cell responses. Immunity. 2020 Oct 13;53(4):864-77.e5. doi: 10.1016/j.immuni.2020.07.026. Epub 2020 Aug 4.

45. Hadjadj J, Yatim N, Barnabei L, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science. 2020 Aug 7;369(6504):718-24. doi: 10.1126/science.abc6027. Epub 2020 Jul 13.


For citations:

Martynov M.Yu., Kutashov V.A., Ulyanova O.V. COVID 19 in a family with rare genetic disease of the nervous system. Neurology, Neuropsychiatry, Psychosomatics. 2022;14(1):108-114.

Views: 283

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

ISSN 2074-2711 (Print)
ISSN 2310-1342 (Online)