An update on the central nervous system manifestations of tuberous sclerosis complex

Abstract

The autosomal dominant disorder tuberous sclerosis complex (TSC) is characterized by an array of manifestations both within and outside of the central nervous system (CNS), including hamartomas and other malformations. TSC is caused by mutations in the TSC1 or TSC2 gene resulting in activation of the mechanistic target of rapamycin (mTOR) signaling pathway. Study of TSC has shed light on the critical role of the mTOR pathway in neurodevelopment. This update reviews the genetic basis of TSC, its cardinal phenotypic CNS features, and recent developments in the field of TSC and other mTOR-altered disorders.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

Gross photographs (a, b) courtesy of Dr. Jeffrey Golden

Fig. 3
Fig. 4

Image (a) courtesy of Dr. Alexander R. Judkins

Fig. 5
Fig. 6

Image courtesy of Dr. Jianling Ji

References

  1. 1.

    Arseni C, Alexianu M, Horvat L, Alexianu D, Petrovici A (1972) Fine structure of atypical cells in tuberous sclerosis. Acta Neuropathol 21:185–193

    CAS  Article  Google Scholar 

  2. 2.

    Au KS, Williams AT, Roach ES, Batchelor L, Sparagana SP, Delgado MR et al (2007) Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med 9:88–100. https://doi.org/10.1097/GIM.0b013e31803068c7

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Barrows BD, Rutkowski MJ, Gultekin SH, Parsa AT, Tihan T (2012) Evidence of ambiguous differentiation and mTOR pathway dysregulation in subependymal giant cell astrocytoma. Turk Patoloji Derg 28:95–103. https://doi.org/10.5146/tjpath.2012.01107

    Article  PubMed  Google Scholar 

  4. 4.

    Bateup HS, Johnson CA, Denefrio CL, Saulnier JL, Kornacker K, Sabatini BL (2013) Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron 78:510–522. https://doi.org/10.1016/j.neuron.2013.03.017

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Blair JD, Hockemeyer D, Bateup HS (2018) Genetically engineered human cortical spheroid models of tuberous sclerosis. Nat Med 24:1568–1578. https://doi.org/10.1038/s41591-018-0139-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Bongaarts A, Giannikou K, Reinten RJ, Anink JJ, Mills JD, Jansen FE et al (2017) Subependymal giant cell astrocytomas in tuberous sclerosis complex have consistent TSC1/TSC2 biallelic inactivation, and no BRAF mutations. Oncotarget 8:95516–95529. https://doi.org/10.18632/oncotarget.20764

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Boronat S, Barber I (2018) Less common manifestations in TSC. Am J Med Genet Part C Semin Med Genet 178:348–354. https://doi.org/10.1002/ajmg.c.31648

    Article  PubMed  Google Scholar 

  8. 8.

    Bourneville D (1880) Contribution à l’étude de l’idiotie. Arch Neurol (Paris) 1:69–91

    Google Scholar 

  9. 9.

    Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469–474. https://doi.org/10.1038/nature26000

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Chan JA, Zhang H, Roberts PS, Jozwiak S, Wieslawa G, Lewin-Kowalik J et al (2004) Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol 63:1236–1242

    CAS  Article  Google Scholar 

  11. 11.

    Crino PB, Trojanowski JQ, Dichter MA, Eberwine J (1996) Embryonic neuronal markers in tuberous sclerosis: single-cell molecular pathology. Proc Natl Acad Sci USA 93:14152–14157

    CAS  Article  Google Scholar 

  12. 12.

    Cuddapah VA, Thompson M, Blount J, Li R, Guleria S, Goyal M (2015) Hemispherectomy for hemimegalencephaly due to tuberous sclerosis and a review of the literature. Pediatr Neurol 53:452–455. https://doi.org/10.1016/j.pediatrneurol.2015.06.020

    Article  PubMed  Google Scholar 

  13. 13.

    Curatolo P, Franz DN, Lawson JA, Yapici Z, Ikeda H, Polster T et al (2018) Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post hoc analysis of the phase 3 EXIST-3 trial. Lancet Child Adolesc Health 2:495–504. https://doi.org/10.1016/s2352-4642(18)30099-3

    Article  PubMed  Google Scholar 

  14. 14.

    D’Gama AM, Geng Y, Couto JA, Martin B, Boyle EA, LaCoursiere CM et al (2015) Mammalian target of rapamycin pathway mutations cause hemimegalencephaly and focal cortical dysplasia. Ann Neurol 77:720–725. https://doi.org/10.1002/ana.24357

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    D’Gama AM, Woodworth MB, Hossain AA, Bizzotto S, Hatem NE, LaCoursiere CM et al (2017) Somatic mutations activating the mTOR pathway in dorsal telencephalic progenitors cause a continuum of cortical dysplasias. Cell Rep 21:3754–3766. https://doi.org/10.1016/j.celrep.2017.11.106

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Davis RL, Nelson E (1961) Unilateral ganglioglioma in a tuberosclerotic brain. J Neuropathol Exp Neurol 20:571–581

    CAS  Article  Google Scholar 

  17. 17.

    de Leon GA, Zaeri N, Foley CM (1988) Olfactory hamartomas in tuberous sclerosis. J Neurol Sci 87:187–194

    Article  Google Scholar 

  18. 18.

    de Vries PJ, Belousova E, Benedik MP, Carter T, Cottin V, Curatolo P et al (2018) TSC-associated neuropsychiatric disorders (TAND): findings from the TOSCA natural history study. Orphanet J Rare Dis 13:157. https://doi.org/10.1186/s13023-018-0901-8

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Dibble CC, Manning BD (2010) The TSC1–TSC2 complex: a key signal-integrating node upstream of TOR. Enzymes 28:21–48

    CAS  Article  Google Scholar 

  20. 20.

    Dragoumi P, O’Callaghan F, Zafeiriou DI (2018) Diagnosis of tuberous sclerosis complex in the fetus. Eur J Paediatr Neurol. https://doi.org/10.1016/j.ejpn.2018.08.005

    Article  PubMed  Google Scholar 

  21. 21.

    European Chromosome 16 Tuberous Sclerosis Consortium (1993) Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305–1315

    Article  Google Scholar 

  22. 22.

    Feldman ME, Shokat KM (2010) New inhibitors of the PI3K–Akt–mTOR pathway: insights into mTOR signaling from a new generation of Tor Kinase Domain Inhibitors (TORKinibs). Curr Top Microbiol Immunol 347:241–262. https://doi.org/10.1007/82_2010_64

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Ferrer I, Fabregues I, Coll J, Ribalta T, Rives A (1984) Tuberous sclerosis: a Golgi study of cortical tuber. Clin Neuropathol 3:47–51

    CAS  PubMed  Google Scholar 

  24. 24.

    Franz DN, Belousova E, Sparagana S, Bebin EM, Frost MD, Kuperman R et al (2016) Long-term use of everolimus in patients with tuberous sclerosis complex: final results from the EXIST-1 study. PLoS One 11:e0158476. https://doi.org/10.1371/journal.pone.0158476

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Franz DN, Leonard J, Tudor C, Chuck G, Care M, Sethuraman G et al (2006) Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 59:490–498. https://doi.org/10.1002/ana.20784

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    French JA, Lawson JA, Yapici Z, Ikeda H, Polster T, Nabbout R et al (2016) Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 388:2153–2163. https://doi.org/10.1016/S0140-6736(16)31419-2

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Gao X, Pan D (2001) TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev 15:1383–1392. https://doi.org/10.1101/gad.901101

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Gedikbasi A, Oztarhan K, Ulker V, Aslan G, Gul A, Sener-Arslan E et al (2011) Prenatal sonographic diagnosis of tuberous sclerosis complex. J Clin Ultrasound 39:427–430. https://doi.org/10.1002/jcu.20857

    Article  PubMed  Google Scholar 

  29. 29.

    Gilboa T, Segel R, Zeligson S, Alterescu G, Ben-Pazi H (2018) Ganglioglioma, epilepsy, and intellectual impairment due to familial TSC1 deletion. J Child Neurol 33:482–486. https://doi.org/10.1177/0883073818767036

    Article  PubMed  Google Scholar 

  30. 30.

    Gusman M, Servaes S, Feygin T, Degenhardt K, Epelman M (2012) Multimodal imaging in the prenatal diagnosis of tuberous sclerosis complex. Case Rep Pediatr 2012:925646. https://doi.org/10.1155/2012/925646

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Henske EP, Scheithauer BW, Short MP, Wollmann R, Nahmias J, Hornigold N et al (1996) Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am J Hum Genet 59:400–406

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Itoua B, Joubert E, Le Bras Y, Picot F, Gautier F, Wertel F et al (1999) What is it? Bourneville tuberous sclerosis associated with an arteriovenous malformation, a pituitary adenoma and 2 arachnoid cysts. J Radiol 80:395–396

    CAS  PubMed  Google Scholar 

  33. 33.

    Jozwiak S, Kotulska K, Berkowitz N, Brechenmacher T, Franz DN (2016) Safety of everolimus in patients younger than 3 years of age: results from EXIST-1, a randomized, controlled clinical trial. J Pediatr 172(151–155):e151. https://doi.org/10.1016/j.jpeds.2016.01.027

    CAS  Article  Google Scholar 

  34. 34.

    Katz JS, Milla SS, Wiggins GC, Devinsky O, Weiner HL, Roth J (2012) Intraventricular lesions in tuberous sclerosis complex: a possible association with the caudate nucleus. J Neurosurg Pediatr 9:406–413. https://doi.org/10.3171/2011.12.PEDS11418

    Article  PubMed  Google Scholar 

  35. 35.

    Kenerson H, Dundon TA, Yeung RS (2005) Effects of rapamycin in the Eker rat model of tuberous sclerosis complex. Pediatr Res 57:67–75. https://doi.org/10.1203/01.PDR.0000147727.78571.07

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Krueger DA, Capal JK, Curatolo P, Devinsky O, Ess K, Tzadok M et al (2018) Short-term safety of mTOR inhibitors in infants and very young children with tuberous sclerosis complex (TSC): multicentre clinical experience. Eur J Paediatr Neurol. https://doi.org/10.1016/j.ejpn.2018.06.007

    Article  PubMed  Google Scholar 

  37. 37.

    Krueger DA, Care MM, Holland K, Agricola K, Tudor C, Mangeshkar P et al (2010) Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 363:1801–1811. https://doi.org/10.1056/NEJMoa1001671

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus Group (2013) Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49:255–265. https://doi.org/10.1016/j.pediatrneurol.2013.08.002

    Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Lee D, Cho YH, Kang SY, Yoon N, Sung CO, Suh YL (2015) BRAF V600E mutations are frequent in dysembryoplastic neuroepithelial tumors and subependymal giant cell astrocytomas. J Surg Oncol 111:359–364. https://doi.org/10.1002/jso.23822

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Lee-Jones L, Aligianis I, Davies PA, Puga A, Farndon PA, Stemmer-Rachamimov A et al (2004) Sacrococcygeal chordomas in patients with tuberous sclerosis complex show somatic loss of TSC1 or TSC2. Genes Chromosom Cancer 41:80–85. https://doi.org/10.1002/gcc.20052

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Li Y, Barkovich MJ, Karch CM, Nillo RM, Fan CC, Broce IJ et al (2018) Regionally specific TSC1 and TSC2 gene expression in tuberous sclerosis complex. Sci Rep 8:13373. https://doi.org/10.1038/s41598-018-31075-4

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Liu J, Reeves C, Michalak Z, Coppola A, Diehl B, Sisodiya SM et al (2014) Evidence for mTOR pathway activation in a spectrum of epilepsy-associated pathologies. Acta Neuropathol Commun 2:71. https://doi.org/10.1186/2051-5960-2-71

    Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Liu W, Yu WM, Zhang J, Chan RJ, Loh ML, Zhang Z et al (2017) Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations. Leukemia 31:1415–1422. https://doi.org/10.1038/leu.2016.326

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Lopes MB, Altermatt HJ, Scheithauer BW, Shepherd CW, VandenBerg SR (1996) Immunohistochemical characterization of subependymal giant cell astrocytomas. Acta Neuropathol 91:368–375

    CAS  Article  Google Scholar 

  45. 45.

    Magri L, Cominelli M, Cambiaghi M, Cursi M, Leocani L, Minicucci F et al (2013) Timing of mTOR activation affects tuberous sclerosis complex neuropathology in mouse models. Dis Model Mech 6:1185–1197. https://doi.org/10.1242/dmm.012096

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Martin KR, Zhou W, Bowman MJ, Shih J, Au KS, Dittenhafer-Reed KE et al (2017) The genomic landscape of tuberous sclerosis complex. Nat Commun 8:15816. https://doi.org/10.1038/ncomms15816

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    McMaster ML, Goldstein AM, Parry DM (2011) Clinical features distinguish childhood chordoma associated with tuberous sclerosis complex (TSC) from chordoma in the general paediatric population. J Med Genet 48:444–449. https://doi.org/10.1136/jmg.2010.085092

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Moon UY, Park JY, Park R, Cho JY, Hughes LJ, McKenna J 3rd et al (2015) Impaired Reelin-Dab1 signaling contributes to neuronal migration deficits of tuberous sclerosis complex. Cell Rep 12:965–978. https://doi.org/10.1016/j.celrep.2015.07.013

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Nardelli E, De Benedictis G, La Stilla G, Nicolardi G (1986) Tuberous sclerosis: a neuropathological and immunohistochemical (PAP) study. Clin Neuropathol 5:261–266

    CAS  PubMed  Google Scholar 

  50. 50.

    Normand EA, Crandall SR, Thorn CA, Murphy EM, Voelcker B, Browning C et al (2013) Temporal and mosaic Tsc1 deletion in the developing thalamus disrupts thalamocortical circuitry, neural function, and behavior. Neuron 78:895–909. https://doi.org/10.1016/j.neuron.2013.03.030

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Northrup H, Krueger DA, International Tuberous Sclerosis Complex Consensus Group (2013) Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49:243–254. https://doi.org/10.1016/j.pediatrneurol.2013.08.001

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    O’Callaghan FJ, Shiell AW, Osborne JP, Martyn CN (1998) Prevalence of tuberous sclerosis estimated by capture-recapture analysis. Lancet 351:1490. https://doi.org/10.1016/S0140-6736(05)78872-3

    Article  PubMed  Google Scholar 

  53. 53.

    O’Rahilly R, Müller F (1994) The embryonic human brain: an atlas of developmental stages. Wiley-Liss, Hoboken

    Google Scholar 

  54. 54.

    Ouyang T, Zhang N, Benjamin T, Wang L, Jiao J, Zhao Y et al (2014) Subependymal giant cell astrocytoma: current concepts, management, and future directions. Childs Nerv Syst 30:561–570. https://doi.org/10.1007/s00381-014-2383-x

    Article  PubMed  Google Scholar 

  55. 55.

    Overwater IE, Swenker R, van der Ende EL, Hanemaayer KB, Hoogeveen-Westerveld M, van Eeghen AM et al (2016) Genotype and brain pathology phenotype in children with tuberous sclerosis complex. Eur J Hum Genet 24:1688–1695. https://doi.org/10.1038/ejhg.2016.85

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Peron A, Au KS, Northrup H (2018) Genetics, genomics, and genotype-phenotype correlations of TSC: insights for clinical practice. Am J Med Genet Part C Semin Med Genet 178:281–290. https://doi.org/10.1002/ajmg.c.31651

    Article  PubMed  Google Scholar 

  57. 57.

    Prabowo AS, Anink JJ, Lammens M, Nellist M, van den Ouweland AM, Adle-Biassette H et al (2013) Fetal brain lesions in tuberous sclerosis complex: TORC1 activation and inflammation. Brain Pathol 23:45–59. https://doi.org/10.1111/j.1750-3639.2012.00616.x

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Ramesh V (2003) Aspects of tuberous sclerosis complex (TSC) protein function in the brain. Biochem Soc Trans 31:579–583. https://doi.org/10.1042/bst0310579

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Roach ES (2016) Applying the lessons of tuberous sclerosis: the 2015 Hower Award Lecture. Pediatr Neurol 63:6–22. https://doi.org/10.1016/j.pediatrneurol.2016.07.003

    Article  PubMed  Google Scholar 

  60. 60.

    Rodrik-Outmezguine VS, Okaniwa M, Yao Z, Novotny CJ, McWhirter C, Banaji A et al (2016) Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature 534:272–276. https://doi.org/10.1038/nature17963

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Rosser T (2018) Neurocutaneous disorders. Continuum (Minneap Minn) 24:96–129. https://doi.org/10.1212/CON.0000000000000562

    Article  Google Scholar 

  62. 62.

    Roth J, Roach ES, Bartels U, Jozwiak S, Koenig MK, Weiner HL et al (2013) Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from the International Tuberous Sclerosis Complex Consensus Conference 2012. Pediatr Neurol 49:439–444. https://doi.org/10.1016/j.pediatrneurol.2013.08.017

    Article  PubMed  Google Scholar 

  63. 63.

    Samueli S, Dressler A, Groppel G, Scholl T, Feucht M (2018) Everolimus in infants with tuberous sclerosis complex-related West syndrome: first results from a single-center prospective observational study. Epilepsia 59:e142–e146. https://doi.org/10.1111/epi.14529

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Sancak O, Nellist M, Goedbloed M, Elfferich P, Wouters C, Maat-Kievit A et al (2005) Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype–phenotype correlations and comparison of diagnostic DNA techniques in Tuberous Sclerosis Complex. Eur J Hum Genet 13:731–741. https://doi.org/10.1038/sj.ejhg.5201402

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Schindler G, Capper D, Meyer J, Janzarik W, Omran H, Herold-Mende C et al (2011) Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 121:397–405. https://doi.org/10.1007/s00401-011-0802-6

    CAS  Article  PubMed  Google Scholar 

  66. 66.

    Schramm C, Fine DM, Edwards MA, Reeb AN, Krenz M (2012) The PTPN11 loss-of-function mutation Q510E-Shp2 causes hypertrophic cardiomyopathy by dysregulating mTOR signaling. Am J Physiol Heart Circ Physiol 302:H231–H243. https://doi.org/10.1152/ajpheart.00665.2011

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Schubert-Bast S, Rosenow F, Klein KM, Reif PS, Kieslich M, Strzelczyk A (2018) The role of mTOR inhibitors in preventing epileptogenesis in patients with TSC: current evidence and future perspectives. Epilepsy Behav. https://doi.org/10.1016/j.yebeh.2018.05.039

    Article  PubMed  Google Scholar 

  68. 68.

    Switon K, Kotulska K, Janusz-Kaminska A, Zmorzynska J, Jaworski J (2017) Molecular neurobiology of mTOR. Neuroscience 341:112–153. https://doi.org/10.1016/j.neuroscience.2016.11.017

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Tatli M, Guzel A (2007) Bilateral temporal arachnoid cysts associated with tuberous sclerosis complex. J Child Neurol 22:775–779. https://doi.org/10.1177/0883073807304014

    Article  PubMed  Google Scholar 

  70. 70.

    Toldo I, Brasson V, Miscioscia M, Pelizza MF, Manara R, Sartori S et al (2018) Tuberous sclerosis-associated neuropsychiatric disorders: a paediatric cohort study. Dev Med Child Neurol. https://doi.org/10.1111/dmcn.14055

    Article  PubMed  Google Scholar 

  71. 71.

    Trombley IK, Mirra SS (1981) Ultrastructure of tuberous sclerosis: cortical tuber and subependymal tumor. Ann Neurol 9:174–181. https://doi.org/10.1002/ana.410090211

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Tsai V, Parker WE, Orlova KA, Baybis M, Chi AW, Berg BD et al (2014) Fetal brain mTOR signaling activation in tuberous sclerosis complex. Cereb Cortex 24:315–327. https://doi.org/10.1093/cercor/bhs310

    Article  PubMed  Google Scholar 

  73. 73.

    van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S et al (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–808

    Article  Google Scholar 

  74. 74.

    Vinters HV, Park SH, Johnson MW, Mischel PS, Catania M, Kerfoot C (1999) Cortical dysplasia, genetic abnormalities and neurocutaneous syndromes. Dev Neurosci 21:248–259. https://doi.org/10.1159/000017404

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    von Recklinghausen F (1862) Ein Herz von einem Neugebore- nen, welches mehrere teils nach aussen, teils nach den Höhlen prominierende Tumoren (Myomen) trug. Verh Ges Geburtsh Monatschr Geburtsk 20:1–2

    Google Scholar 

  76. 76.

    Wataya-Kaneda M (2015) Mammalian target of rapamycin and tuberous sclerosis complex. J Dermatol Sci 79:93–100. https://doi.org/10.1016/j.jdermsci.2015.04.005

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Yasin SA, Latak K, Becherini F, Ganapathi A, Miller K, Campos O et al (2010) Balloon cells in human cortical dysplasia and tuberous sclerosis: isolation of a pathological progenitor-like cell. Acta Neuropathol 120:85–96. https://doi.org/10.1007/s00401-010-0677-y

    Article  PubMed  Google Scholar 

  78. 78.

    Yates JR, Maclean C, Higgins JN, Humphrey A, le Marechal K, Clifford M et al (2011) The Tuberous Sclerosis 2000 Study: presentation, initial assessments and implications for diagnosis and management. Arch Dis Child 96:1020–1025. https://doi.org/10.1136/adc.2011.211995

    Article  PubMed  Google Scholar 

  79. 79.

    Yeung RS, Katsetos CD, Klein-Szanto A (1997) Subependymal astrocytic hamartomas in the Eker rat model of tuberous sclerosis. Am J Pathol 151:1477–1486

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Zhou J, Shrikhande G, Xu J, McKay RM, Burns DK, Johnson JE et al (2011) Tsc1 mutant neural stem/progenitor cells exhibit migration deficits and give rise to subependymal lesions in the lateral ventricle. Genes Dev 25:1595–1600. https://doi.org/10.1101/gad.16750211

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Zordan P, Cominelli M, Cascino F, Tratta E, Poliani PL, Galli R (2018) Tuberous sclerosis complex-associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt. J Clin Investig 128:1688–1706. https://doi.org/10.1172/jci96342

    Article  PubMed  Google Scholar 

  82. 82.

    Zou J, Zhang B, Gutmann DH, Wong M (2017) Postnatal reduction of tuberous sclerosis complex 1 expression in astrocytes and neurons causes seizures in an age-dependent manner. Epilepsia 58:2053–2063. https://doi.org/10.1111/epi.13923

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Zucco AJ, Pozzo VD, Afinogenova A, Hart RP, Devinsky O, D’Arcangelo G (2018) Neural progenitors derived from Tuberous Sclerosis Complex patients exhibit attenuated PI3K/AKT signaling and delayed neuronal differentiation. Mol Cell Neurosci 92:149–163. https://doi.org/10.1016/j.mcn.2018.08.004

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author would like to thank Dr. Jaclyn Biegel, Dr. Jianling Ji, Dr. Tena Rosser, and Dr. Benita Tamrazi for their helpful comments on the manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jennifer A. Cotter.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cotter, J.A. An update on the central nervous system manifestations of tuberous sclerosis complex. Acta Neuropathol 139, 613–624 (2020). https://doi.org/10.1007/s00401-019-02003-1

Download citation

Keywords

  • Tuberous sclerosis
  • TSC1
  • TSC2
  • Hamartin
  • Tuberin
  • mTOR
  • Tuber
  • Subependymal nodule
  • Subependymal giant cell astrocytoma (SEGA)
  • Focal cortical dysplasia