RSS-Feed abonnieren
Bitte kopieren Sie die angezeigte URL und fügen sie dann in Ihren RSS-Reader ein.
https://www.thieme-connect.de/rss/thieme/de/10.1055-s-00029030.xml
PDF herunterladen
Journal of Pediatric Neurology 2023; 21(04): 235-247
DOI: 10.1055/s-0041-1727142
DOI: 10.1055/s-0041-1727142
Review Article
TSC1 and TSC2: Tuberous Sclerosis Complex and Its Related Epilepsy Phenotype
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by a multisystemic involvement. In TSC, reduced function of TSC1 and TSC2 genes products (hamartin and tuberin, respectively) leads to an hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and to a consequent cell growth dysregulation. In TSC patients, neurological and neuropsychiatric manifestations, especially epilepsy and neuropsychiatric comorbidities such as autism or intellectual disability, represent the most disabling features. In particular, epilepsy occurrs up to 80% of patients, is often drug resistant and is frequently associated with neurological impairment. Due to the burden of this morbidity, different treatment strategies have been proposed with the purpose to make patients epilepsy free, such as the use of different antiepileptic drugs like vigabatrin, carbamazepine, valproic acid, and levetiracetam. More recently, a mTOR inhibitor (i.e. everolimus) has showed promising results in terms of seizures reduction.
* The authors have equally contributed to this article.
Publikationsverlauf
Eingereicht: 20. Februar 2021
Angenommen: 21. Februar 2021
Artikel online veröffentlicht:
21. Mai 2021
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006; 355 (13) 1345-1356
- 2
Curatolo P,
Bombardieri R,
Jozwiak S.
Tuberous sclerosis. Lancet 2008; 372 (9639): 657-668
MissingFormLabel
- 3 Gómez MR. History of the tuberous sclerosis complex. Brain Dev 1995; 17 (Suppl): 55-57
- 4 Huang J, Manning BD. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 2008; 412 (02) 179-190
- 5 Salussolia CL, Klonowska K, Kwiatkowski DJ, Sahin M. Genetic etiologies, diagnosis, and treatment of tuberous sclerosis complex. Annu Rev Genomics Hum Genet 2019; 20: 217-240
- 6
Curatolo P,
Moavero R,
de Vries PJ.
Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol
2015; 14 (07) 733-745
MissingFormLabel
- 7 Connor JM, Stephenson JB, Hadley MD. Non-penetrance in tuberous sclerosis. Lancet 1986; 2 (8518): 1275
- 8 Webb DW, Osborne JP. Non-penetrance in tuberous sclerosis. J Med Genet 1991; 28 (06) 417-419
- 9 Rose VM, Au KS, Pollom G, Roach ES, Prashner HR, Northrup H. Germ-line mosaicism in tuberous sclerosis: how common?. Am J Hum Genet 1999; 64 (04) 986-992
- 10 Canevini MP, Kotulska-Jozwiak K, Curatolo P. et al. Current concepts on epilepsy management in tuberous sclerosis complex. Am J Med Genet C Semin Med Genet 2018; 178 (03) 299-308
- 11 Curatolo P. Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr Neurol 2015; 52 (03) 281-289
- 12 Saxena A, Sampson JR. Epilepsy in tuberous sclerosis: phenotypes, mechanisms, and treatments. Semin Neurol 2015; 35 (03) 269-276
- 13 de Groen AC, Bolton J, Bergin AM, Sahin M, Peters JM. The evolution of subclinical seizures in children with tuberous sclerosis complex. J Child Neurol 2019; 34 (12) 770-777
- 14 Ruggieri M, Rizzo R, Pavone P, Baieli S, Sorge G, Happle R. Temporal triangular alopecia in association with mental retardation and epilepsy in a mother and daughter. Arch Dermatol 2000; 136 (03) 426-427
- 15 Ruggieri M, Iannetti P, Clementi M. et al. Neurofibromatosis type 1 and infantile spasms. Childs Nerv Syst 2009; 25 (02) 211-216
- 16 Jóźwiak S, Kotulska K, Domańska-Pakieła D. et al. Antiepileptic treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. Eur J Paediatr Neurol 2011; 15 (05) 424-431
- 17 Curatolo P, Jóźwiak S, Nabbout R. TSC Consensus Meeting for SEGA and Epilepsy Management. Management of epilepsy associated with tuberous sclerosis complex (TSC): clinical recommendations. Eur J Paediatr Neurol 2012; 16 (06) 582-586
- 18 van Slegtenhorst M, de Hoogt R, Hermans C. et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997; 277 (5327): 805-808
- 19 Hoogeveen-Westerveld M, Wentink M, van den Heuvel D. et al. Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with tuberous sclerosis complex. Hum Mutat 2011; 32 (04) 424-435
- 20 Choi JE, Chae JH, Hwang YS, Kim KJ. Mutational analysis of TSC1 and TSC2 in Korean patients with tuberous sclerosis complex. Brain Dev 2006; 28 (07) 440-446
- 21 Lee DF, Kuo HP, Chen CT. et al. IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 2007; 130 (03) 440-455
- 22 Mozaffari M, Hoogeveen-Westerveld M, Kwiatkowski D. et al. Identification of a region required for TSC1 stability by functional analysis of TSC1 missense mutations found in individuals with tuberous sclerosis complex. BMC Med Genet 2009; 10: 88
- 23 Nellist M, van den Heuvel D, Schluep D. et al. Missense mutations to the TSC1 gene cause tuberous sclerosis complex. Eur J Hum Genet 2009; 17 (03) 319-328
- 24 European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993; 75 (07) 1305-1315
- 25 van Bakel I, Sepp T, Ward S, Yates JR, Green AJ. Mutations in the TSC2 gene: analysis of the complete coding sequence using the protein truncation test (PTT). Hum Mol Genet 1997; 6 (09) 1409-1414
- 26 Maheshwar MM, Cheadle JP, Jones AC. et al. The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis. Hum Mol Genet 1997; 6 (11) 1991-1996
- 27 Hoogeveen-Westerveld M, Ekong R, Povey S. et al. Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex. Hum Mutat 2013; 34 (01) 167-175
- 28 Brook-Carter PT, Peral B, Ward CJ. et al. Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease--a contiguous gene syndrome. Nat Genet 1994; 8 (04) 328-332
- 29
Sancak O,
Nellist M,
Goedbloed M.
et al.
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 2005; 13 (06) 731-741
MissingFormLabel
- 30 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; 9 (02) 88-100
- 31 Kozlowski P, Roberts P, Dabora S. et al. Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations. Hum Genet 2007; 121 (3-4): 389-400
- 32 Qin W, Kozlowski P, Taillon BE. et al. Ultra deep sequencing detects a low rate of mosaic mutations in tuberous sclerosis complex. Hum Genet 2010; 127 (05) 573-582
- 33 Niida Y, Lawrence-Smith N, Banwell A. et al. Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis. Hum Mutat 1999; 14 (05) 412-422
- 34 Jones AC, Shyamsundar MM, Thomas MW. et al. Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am J Hum Genet 1999; 64 (05) 1305-1315
- 35 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; 68 (01) 64-80
- 36 Langkau N, Martin N, Brandt R. et al. TSC1 and TSC2 mutations in tuberous sclerosis, the associated phenotypes and a model to explain observed TSC1/ TSC2 frequency ratios. Eur J Pediatr 2002; 161 (07) 393-402
- 37 Li Y, Corradetti MN, Inoki K, Guan KL. TSC2: filling the GAP in the mTOR signaling pathway. Trends Biochem Sci 2004; 29 (01) 32-38
- 38 Hansmann P, Brückner A, Kiontke S. et al. Structure of the TSC2 GAP domain: mechanistic insight into catalysis and pathogenic mutations. Structure 2020; 28 (08) 933-942.e4
- 39
Portocarrero LKL,
Quental KN,
Samorano LP,
Oliveira ZNP,
Rivitti-Machado MCDM.
Tuberous sclerosis complex: review based on new diagnostic criteria. An Bras Dermatol
2018; 93: 323-331
MissingFormLabel
- 40 Goncharova EA, Goncharov DA, Eszterhas A. et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J Biol Chem 2002; 277 (34) 30958-30967
- 41 Lim JS, Gopalappa R, Kim SH. et al. Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia. Am J Hum Genet 2017; 100 (03) 454-472
- 42 Palmini A, Najm I, Avanzini G. et al. Terminology and classification of the cortical dysplasias. Neurology 2004; 62 (06, Suppl 3): S2-S8
- 43 Møller RS, Weckhuysen S, Chipaux M. et al. Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy. Neurol Genet 2016; 2 (06) e118
- 44 Sorge G, Ruggieri M, Polizzi A, Scuderi A, Di Pietro M. SHORT syndrome: a new case with probable autosomal dominant inheritance. Am J Med Genet 1996; 61 (02) 178-181
- 45 Sato T, Seyama K, Fujii H. et al. Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis. J Hum Genet 2002; 47 (01) 20-28
- 46 Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci U S A 2000; 97 (11) 6085-6090
- 47 Johnson SR, Taveira-DaSilva AM, Moss J. Lymphangioleiomyomatosis. Clin Chest Med 2016; 37 (03) 389-403
- 48 Hammes SR, Krymskaya VP. Targeted approaches toward understanding and treating pulmonary lymphangioleiomyomatosis (LAM). Horm Cancer 2013; 4 (02) 70-77
- 49 Brigo F, Lattanzi S, Trinka E. et al. First descriptions of tuberous sclerosis by Désiré-Magloire Bourneville (1840-1909). Neuropathology 2018; 38 (06) 577-582
- 50 Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci 1991; 615: 125-127
- 51 O'Callaghan FJ, Shiell AW, Osborne JP, Martyn CN. Prevalence of tuberous sclerosis estimated by capture-recapture analysis. Lancet 1998; 351 (9114): 1490
- 52 Ruggieri M, Milone P, Pavone P. et al. Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients. Am J Med Genet A 2012; 158A (11) 2870-2880
- 53 Ruggieri M, Iannetti P, Pavone L. Delineation of a newly recognized neurocutaneous malformation syndrome with “cutis tricolor”. Am J Med Genet A 2003; 120A (01) 110-116
- 54 Ruggieri M, Praticò AD, Serra A. et al. Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies. Acta Otorhinolaryngol Ital 2016; 36 (05) 345-367
- 55 Dragoumi P, O'Callaghan F, Zafeiriou DI. Diagnosis of tuberous sclerosis complex in the fetus. Eur J Paediatr Neurol 2018; 22 (06) 1027-1034
- 56 Mlczoch E, Hanslik A, Luckner D, Kitzmüller E, Prayer D, Michel-Behnke I. Prenatal diagnosis of giant cardiac rhabdomyoma in tuberous sclerosis complex: a new therapeutic option with everolimus. Ultrasound Obstet Gynecol 2015; 45 (05) 618-621
- 57 Jost CJ, Gloviczki P, Edwards WD, Stanson AW, Joyce JW, Pairolero PC. Aortic aneurysms in children and young adults with tuberous sclerosis: report of two cases and review of the literature. J Vasc Surg 2001; 33 (03) 639-642
- 58 Sanchez FW, Vujic I, Ayres RI, Curry NS, Gobien RP. Hemorrhagic renal angiomyolipoma: superselective renal arterial embolization for preservation of renal function. Cardiovasc Intervent Radiol 1985; 8 (01) 39-42
- 59 Libby PA, Maitem AN, Strauss EB. Axillary artery aneurysm in a patient with tuberous sclerosis. Pediatr Radiol 1989; 20 (1-2): 94
- 60 Jarrett ME, Libertiny G, Gould SJ, Morris P. Carotid artery aneurysm in a child with tuberous sclerosis. Eur J Vasc Endovasc Surg 1998; 16 (01) 80-81
- 61 Shields JA, Eagle Jr RC, Shields CL, Marr BP. Aggressive retinal astrocytomas in four patients with tuberous sclerosis complex. Trans Am Ophthalmol Soc 2004; 102: 139-147 , discussion 147–148
- 62 Marciano S, Mutolo MG, Siracusano M, Moavero R, Curatolo P, Emberti Gialloreti L. Everolimus for retinal astrocytic hamartomas in tuberous sclerosis complex. Ophthalmol Retina 2018; 2 (03) 257-260
- 63 Ewalt DH, Sheffield E, Sparagana SP, Delgado MR, Roach ES. Renal lesion growth in children with tuberous sclerosis complex. J Urol 1998; 160 (01) 141-145
- 64 Nelson CP, Sanda MG. Contemporary diagnosis and management of renal angiomyolipoma. J Urol 2002; 168 (4 Pt 1): 1315-1325
- 65 Robert A, Leroy V, Riquet A, Gogneaux L, Boutry N, Avni FE. Renal involvement in tuberous sclerosis complex with emphasis on cystic lesions. Radiol Med (Torino) 2016; 121 (05) 402-408
- 66 Rakowski SK, Winterkorn EB, Paul E, Steele DJ, Halpern EF, Thiele EA. Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney Int 2006; 70 (10) 1777-1782
- 67 Bissler JJ, Christopher Kingswood J. Renal manifestation of tuberous sclerosis complex. Am J Med Genet C Semin Med Genet 2018; 178 (03) 338-347
- 68 Sampson JR, Maheshwar MM, Aspinwall R. et al. Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene. Am J Hum Genet 1997; 61 (04) 843-851
- 69 Kakkar A, Vallonthaiel AG, Sharma MC, Bora G, Panda A, Seth A. Composite renal cell carcinoma and angiomyolipoma in a patient with Tuberous sclerosis: a diagnostic dilemma. Can Urol Assoc J 2015; 9 (7-8): E507-E510
- 70 Kingswood JC, Bruzzi P, Curatolo P. et al. TOSCA - first international registry to address knowledge gaps in the natural history and management of tuberous sclerosis complex. Orphanet J Rare Dis 2014; 9: 182
- 71 Costello LC, Hartman TE, Ryu JH. High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc 2000; 75 (06) 591-594
- 72 Mavroudi M, Zarogoulidis P, Katsikogiannis N. et al. Lymphangioleiomyomatosis: current and future. J Thorac Dis 2013; 5 (01) 74-79
- 73 Cudzilo CJ, Szczesniak RD, Brody AS. et al. Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest 2013; 144 (02) 578-585
- 74 Franz DN, Brody A, Meyer C. et al. Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med 2001; 164 (04) 661-668
- 75 Pannu BS, Apala DR, Kotecha A, Boland JM, Iyer VN. Multifocal micronodular pneumocyte hyperplasia (MMPH) in a patient with tuberous sclerosis-evidence for long term stability. Respir Med Case Rep 2017; 20: 113-115
- 76 von Ranke FM, Zanetti G. e Silva JL, et al. Tuberous sclerosis complex: state-of-the-art review with a focus on pulmonary involvement. Lung 2015; 193 (05) 619-627
- 77 Dworakowska D, Grossman AB. Are neuroendocrine tumours a feature of tuberous sclerosis? A systematic review. Endocr Relat Cancer 2009; 16 (01) 45-58
- 78 Wong M, Crino PB. Tuberous sclerosis and epilepsy: role of astrocytes. Glia 2012; 60 (08) 1244-1250
- 79 Roth J, Roach ES, Bartels U. et al. Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from the International Tuberous Sclerosis Complex Consensus Conference 2012. Pediatr Neurol 2013; 49 (06) 439-444
- 80 Krishnan A, Kaza RK, Vummidi DR. Cross-sectional imaging review of tuberous sclerosis. Radiol Clin North Am 2016; 54 (03) 423-440
- 81 Sharma MC, Ralte AM, Gaekwad S, Santosh V, Shankar SK, Sarkar C. Subependymal giant cell astrocytoma--a clinicopathological study of 23 cases with special emphasis on histogenesis. Pathol Oncol Res 2004; 10 (04) 219-224
- 82 Pavone P, Praticò AD, Vitaliti G. et al. Hydranencephaly: cerebral spinal fluid instead of cerebral mantles. Ital J Pediatr 2014; 40: 79
- 83 Curatolo P, Verdecchia M, Bombardieri R. Tuberous sclerosis complex: a review of neurological aspects. Eur J Paediatr Neurol 2002; 6 (01) 15-23
- 84
Henske EP,
Jóźwiak S,
Kingswood JC,
Sampson JR,
Thiele EA.
Tuberous sclerosis complex. Nat Rev Dis Primers 2016; 2: 16035
MissingFormLabel
- 85 Lionetti E, Leonardi S, Franzonello C, Mancardi M, Ruggieri M, Catassi C. Gluten psychosis: confirmation of a new clinical entity. Nutrients 2015; 7 (07) 5532-5539
- 86
Northrup H,
Krueger DA.
International Tuberous Sclerosis Complex Consensus Group.
Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012
Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;
49 (04) 243-254
MissingFormLabel
- 87 Krueger DA, Northrup H. International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49 (04) 255-265
- 88 de Vries PJ, Wilde L, de Vries MC, Moavero R, Pearson DA, Curatolo P. A clinical update on tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Am J Med Genet C Semin Med Genet 2018; 178 (03) 309-320
- 89 La Mendola F, Fatuzzo V, Smilari P. et al. Multiseptate gallbladder in a child: a possible cause of poor growth?. J Pediatr Gastroenterol Nutr 2019; 68 (01) e13
- 90 Ruggieri M, Polizzi A, Marceca GP, Catanzaro S, Praticò AD, Di Rocco C. Introduction to phacomatoses (neurocutaneous disorders) in childhood. Childs Nerv Syst 2020; 36 (10) 2229-2268
- 91 Young LR, Inoue Y, McCormack FX. Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis. N Engl J Med 2008; 358 (02) 199-200
- 92 Young LR, Vandyke R, Gulleman PM. et al. Serum vascular endothelial growth factor-D prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest 2010; 138 (03) 674-681
- 93 Moavero R, Pinci M, Bombardieri R, Curatolo P. The management of subependymal giant cell tumors in tuberous sclerosis: a clinician's perspective. Childs Nerv Syst 2011; 27 (08) 1203-1210
- 94 Berhouma M. Management of subependymal giant cell tumors in tuberous sclerosis complex: the neurosurgeon's perspective. World J Pediatr 2010; 6 (02) 103-110
- 95 Chung TK, Lynch ER, Fiser CJ. et al. Psychiatric comorbidity and treatment response in patients with tuberous sclerosis complex. Ann Clin Psychiatry 2011; 23 (04) 263-269
- 96 Dabora SL, Franz DN, Ashwal S. et al. Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease. PLoS One 2011; 6 (09) e23379
- 97 Davies DM, de Vries PJ, Johnson SR. et al. Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial. Clin Cancer Res 2011; 17 (12) 4071-4081
- 98 Bissler JJ, McCormack FX, Young LR. et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008; 358 (02) 140-151
- 99 Bissler JJ, Kingswood JC, Radzikowska E. et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2013; 381 (9869): 817-824
- 100 Bissler JJ, Racadio J, Donnelly LF, Johnson ND. Reduction of postembolization syndrome after ablation of renal angiomyolipoma. Am J Kidney Dis 2002; 39 (05) 966-971
- 101 Flum AS, Hamoui N, Said MA. et al. Update on the diagnosis and management of renal angiomyolipoma. J Urol 2016; 195 (4 Pt 1): 834-846
- 102 Patel U, Simpson E, Kingswood JC, Saggar-Malik AK. Tuberose sclerosis complex: analysis of growth rates aids differentiation of renal cell carcinoma from atypical or minimal-fat-containing angiomyolipoma. Clin Radiol 2005; 60 (06) 665-673 , discussion 663–664
- 103 Mourikis D, Chatziioannou A, Antoniou A, Kehagias D, Gikas D, Vlahos L. Selective arterial embolization in the management of symptomatic renal angiomyolipomas. Eur J Radiol 1999; 32 (03) 153-159
- 104 McCormack FX, Inoue Y, Moss J. et al; National Institutes of Health Rare Lung Diseases Consortium, MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364 (17) 1595-1606
- 105 Haemel AK, O'Brian AL, Teng JM. Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol 2010; 146 (07) 715-718
- 106 Koenig MK, Hebert AA, Roberson J. et al. Topical rapamycin therapy to alleviate the cutaneous manifestations of tuberous sclerosis complex: a double-blind, randomized, controlled trial to evaluate the safety and efficacy of topically applied rapamycin. Drugs R D 2012; 12 (03) 121-126
- 107 Papadavid E, Markey A, Bellaney G, Walker NPJ. Carbon dioxide and pulsed dye laser treatment of angiofibromas in 29 patients with tuberous sclerosis. Br J Dermatol 2002; 147 (02) 337-342
- 108 Weinberger CH, Endrizzi B, Hook KP, Lee PK. Treatment of angiofibromas of tuberous sclerosis with 5-aminolevulinic acid blue light photodynamic therapy followed by immediate pulsed dye laser. Dermatol Surg 2009; 35 (11) 1849-1851
- 109 Weiss ET, Geronemus RG. New technique using combined pulsed dye laser and fractional resurfacing for treating facial angiofibromas in tuberous sclerosis. Lasers Surg Med 2010; 42 (05) 357-360
- 110 Amin S, Lux A, Calder N, Laugharne M, Osborne J, O'callaghan F. Causes of mortality in individuals with tuberous sclerosis complex. Dev Med Child Neurol 2017; 59 (06) 612-617
- 111 Shepherd CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 1991; 66 (08) 792-796
- 112 Randle SC. Tuberous sclerosis complex: a review. Pediatr Ann 2017; 46 (04) e166-e171
- 113 Avgeris S, Fostira F, Vagena A. et al. Mutational analysis of TSC1 and TSC2 genes in tuberous sclerosis complex patients from Greece. Sci Rep 2017; 7 (01) 16697
- 114 Curatolo P, Moavero R, Roberto D, Graziola F. Genotype/phenotype correlations in tuberous sclerosis complex. Semin Pediatr Neurol 2015; 22 (04) 259-273
- 115 Zeng LH, Rensing NR, Zhang B, Gutmann DH, Gambello MJ, Wong M. Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex. Hum Mol Genet 2011; 20 (03) 445-454
- 116 Yang P, Cornejo KM, Sadow PM. et al. Renal cell carcinoma in tuberous sclerosis complex. Am J Surg Pathol 2014; 38 (07) 895-909
- 117 Kothare SV, Singh K, Chalifoux JR. et al. Severity of manifestations in tuberous sclerosis complex in relation to genotype. Epilepsia 2014; 55 (07) 1025-1029
- 118 Numis AL, Major P, Montenegro MA, Muzykewicz DA, Pulsifer MB, Thiele EA. Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex. Neurology 2011; 76 (11) 981-987
- 119 van Eeghen AM, Black ME, Pulsifer MB, Kwiatkowski DJ, Thiele EA. Genotype and cognitive phenotype of patients with tuberous sclerosis complex. Eur J Hum Genet 2012; 20 (05) 510-515
- 120 Jansen AC, Sancak O, D'Agostino MD. et al. Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation. Ann Neurol 2006; 60 (05) 528-539
- 121 Mayer K, Goedbloed M, van Zijl K, Nellist M, Rott HD. Characterisation of a novel TSC2 missense mutation in the GAP related domain associated with minimal clinical manifestations of tuberous sclerosis. J Med Genet 2004; 41 (05) e64
- 122 Wentink M, Nellist M, Hoogeveen-Westerveld M. et al. Functional characterization of the TSC2 c.3598C>T (p.R1200W) missense mutation that co-segregates with tuberous sclerosis complex in mildly affected kindreds. Clin Genet 2012; 81 (05) 453-461
- 123 O'Connor SE, Kwiatkowski DJ, Roberts PS, Wollmann RL, Huttenlocher PR. A family with seizures and minor features of tuberous sclerosis and a novel TSC2 mutation. Neurology 2003; 61 (03) 409-412
- 124 Northrup H, Koenig MK, Pearson DA, Au KS. Tuberous sclerosis complex. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A. eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020
- 125 Magri L, Cambiaghi M, Cominelli M. et al. Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of tuberous sclerosis complex-associated lesions. Cell Stem Cell 2011; 9 (05) 447-462
- 126 Costa V, Aigner S, Vukcevic M. et al. mTORC1 inhibition corrects neurodevelopmental and synaptic alterations in a human stem cell model of tuberous sclerosis. Cell Rep 2016; 15 (01) 86-95
- 127 Paliouras GN, Hamilton LK, Aumont A, Joppé SE, Barnabé-Heider F, Fernandes KJ. Mammalian target of rapamycin signaling is a key regulator of the transit-amplifying progenitor pool in the adult and aging forebrain. J Neurosci 2012; 32 (43) 15012-15026
- 128 Magri L, Galli R. mTOR signaling in neural stem cells: from basic biology to disease. Cell Mol Life Sci 2013; 70 (16) 2887-2898
- 129 Way SW, McKenna III J, Mietzsch U, Reith RM, Wu HC, Gambello MJ. Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse. Hum Mol Genet 2009; 18 (07) 1252-1265
- 130 Ercan E, Han JM, Di Nardo A. et al. Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex. J Exp Med 2017; 214 (03) 681-697
- 131 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; 8 (01) 94
- 132 Feliciano DM, Su T, Lopez J, Platel JC, Bordey A. Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice. J Clin Invest 2011; 121 (04) 1596-1607
- 133 Lin TV, Hsieh L, Kimura T, Malone TJ, Bordey A. Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration. Proc Natl Acad Sci U S A 2016; 113 (40) 11330-11335
- 134 Choi YJ, Di Nardo A, Kramvis I. et al. Tuberous sclerosis complex proteins control axon formation. Genes Dev 2008; 22 (18) 2485-2495
- 135 Gong X, Zhang L, Huang T. et al. Activating the translational repressor 4E-BP or reducing S6K-GSK3β activity prevents accelerated axon growth induced by hyperactive mTOR in vivo. Hum Mol Genet 2015; 24 (20) 5746-5758
- 136 LiCausi F, Hartman NW. Role of mTOR complexes in neurogenesis. Int J Mol Sci 2018; 19: 1544
- 137 Curatolo P, Moavero R, van Scheppingen J, Aronica E. mTOR dysregulation and tuberous sclerosis-related epilepsy. Expert Rev Neurother 2018; 18 (03) 185-201
- 138 Talos DM, Sun H, Kosaras B. et al. Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia. Ann Neurol 2012; 71 (04) 539-551
- 139 Fu C, Cawthon B, Clinkscales W, Bruce A, Winzenburger P, Ess KC. GABAergic interneuron development and function is modulated by the Tsc1 gene. Cereb Cortex 2012; 22 (09) 2111-2119
- 140 Ruppe V, Dilsiz P, Reiss CS. et al. Developmental brain abnormalities in tuberous sclerosis complex: a comparative tissue analysis of cortical tubers and perituberal cortex. Epilepsia 2014; 55 (04) 539-550
- 141 Cusmai R, Moavero R, Bombardieri R, Vigevano F, Curatolo P. Long-term neurological outcome in children with early-onset epilepsy associated with tuberous sclerosis. Epilepsy Behav 2011; 22 (04) 735-739
- 142 Zeng LH, Xu L, Gutmann DH, Wong M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol 2008; 63 (04) 444-453
- 143 Zhu F, Kai J, Chen L. et al. Akt inhibitor perifosine prevents epileptogenesis in a rat model of temporal lobe epilepsy. Neurosci Bull 2018; 34 (02) 283-290
- 144 Jóźwiak S, Kotulska K. Prevention of epileptogenesis: a new goal for epilepsy therapy. Pediatr Neurol 2014; 51 (06) 758-759
- 145 Camposano SE, Major P, Halpern E, Thiele EA. Vigabatrin in the treatment of childhood epilepsy: a retrospective chart review of efficacy and safety profile. Epilepsia 2008; 49 (07) 1186-1191
- 146 Hussain SA, Schmid E, Peters JM. et al; Tuberous Sclerosis Complex Autism Center of Excellence Network. High vigabatrin dosage is associated with lower risk of infantile spasms relapse among children with tuberous sclerosis complex. Epilepsy Res 2018; 148: 1-7
- 147 Jammoul F, Wang Q, Nabbout R. et al. Taurine deficiency is a cause of vigabatrin-induced retinal phototoxicity. Ann Neurol 2009; 65 (01) 98-107
- 148 Curatolo P, Nabbout R, Lagae L. et al. Management of epilepsy associated with tuberous sclerosis complex: Updated clinical recommendations. Eur J Paediatr Neurol 2018; 22 (05) 738-748
- 149 Vigevano F, Cilio MR. Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study. Epilepsia 1997; 38 (12) 1270-1274
- 150 Pratico AD, Longo L, Mansueto S. et al. Off-label use of drugs and adverse drug reactions in pediatric units: a prospective, multicenter study. Curr Drug Saf 2018; 13 (03) 200-207
- 151 Moavero R, Cerminara C, Curatolo P. Epilepsy secondary to tuberous sclerosis: lessons learned and current challenges. Childs Nerv Syst 2010; 26 (11) 1495-1504
- 152 Franz DN, Lawson JA, Yapici Z. et al. Everolimus for treatment-refractory seizures in TSC: extension of a randomized controlled trial. Neurol Clin Pract 2018; 8 (05) 412-420
- 153 Krueger DA, Wilfong AA, Mays M. et al. Long-term treatment of epilepsy with everolimus in tuberous sclerosis. Neurology 2016; 87 (23) 2408-2415
- 154 van der Poest Clement E, Jansen FE, Braun KPJ, Peters JM. Update on drug management of refractory epilepsy in tuberous sclerosis complex. Paediatr Drugs 2020; 22 (01) 73-84
- 155 Davies M, Saxena A, Kingswood JC. Management of everolimus-associated adverse events in patients with tuberous sclerosis complex: a practical guide. Orphanet J Rare Dis 2017; 12 (01) 35
- 156 Samueli S, Abraham K, Dressler A. et al. Efficacy and safety of everolimus in children with TSC - associated epilepsy - Pilot data from an open single-center prospective study. Orphanet J Rare Dis 2016; 11 (01) 145
- 157 Krueger DA, Capal JK, Curatolo P. et al; TSCure Research Group. Short-term safety of mTOR inhibitors in infants and very young children with tuberous sclerosis complex (TSC): multicentre clinical experience. Eur J Paediatr Neurol 2018; 22 (06) 1066-1073
- 158 Falsaperla R, D'Angelo G, Praticò AD. et al. Ketogenic diet for infants with epilepsy: a literature review. Epilepsy Behav 2020; 112: 107361
- 159 Ruggieri M, Milone P, Pavone P. et al. Nevus vascularis mixtus (cutaneous vascular twin nevi) associated with intracranial vascular malformation of the Dyke-Davidoff-Masson type in two patients. Am J Med Genet A 2012; 158A: 2870-2880
- 160 Coppola G, Klepper J, Ammendola E. et al. The effects of the ketogenic diet in refractory partial seizures with reference to tuberous sclerosis. Eur J Paediatr Neurol 2006; 10 (03) 148-151
- 161 Kossoff EH, Thiele EA, Pfeifer HH, McGrogan JR, Freeman JM. Tuberous sclerosis complex and the ketogenic diet. Epilepsia 2005; 46 (10) 1684-1686
- 162 Bough KJ, Rho JM. Anticonvulsant mechanisms of the ketogenic diet. Epilepsia 2007; 48 (01) 43-58
- 163 Vonck K, De Herdt V, Bosman T, Dedeurwaerdere S, Van Laere K, Boon P. Thalamic and limbic involvement in the mechanism of action of vagus nerve stimulation, a SPECT study. Seizure 2008; 17 (08) 699-706
- 164 Marrosu F, Serra A, Maleci A, Puligheddu M, Biggio G, Piga M. Correlation between GABA(A) receptor density and vagus nerve stimulation in individuals with drug-resistant partial epilepsy. Epilepsy Res 2003; 55 (1-2): 59-70
- 165 Mikati MA, Ataya NF, El-Ferezli JC. et al. Quality of life after vagal nerve stimulator insertion. Epileptic Disord 2009; 11 (01) 67-74
- 166 Devinsky O, Cross JH, Laux L. et al; Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 2017; 376 (21) 2011-2020
- 167 Devinsky O, Patel AD, Cross JH. et al; GWPCARE3 Study Group. Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome. N Engl J Med 2018; 378 (20) 1888-1897
- 168 Reddy DS, Golub VM. The pharmacological basis of cannabis therapy for epilepsy. J Pharmacol Exp Ther 2016; 357 (01) 45-55
- 169 Fallah A, Guyatt GH, Snead III OC. et al. Predictors of seizure outcomes in children with tuberous sclerosis complex and intractable epilepsy undergoing resective epilepsy surgery: an individual participant data meta-analysis. PLoS One 2013; 8 (02) e53565
- 170 Jansen FE, van Huffelen AC, Algra A, van Nieuwenhuizen O. Epilepsy surgery in tuberous sclerosis: a systematic review. Epilepsia 2007; 48 (08) 1477-1484
- 171 Madhavan D, Schaffer S, Yankovsky A. et al. Surgical outcome in tuberous sclerosis complex: a multicenter survey. Epilepsia 2007; 48 (08) 1625-1628
- 172 Weiner HL, Carlson C, Ridgway EB. et al. Epilepsy surgery in young children with tuberous sclerosis: results of a novel approach. Pediatrics 2006; 117 (05) 1494-1502
- 173 Curatolo P, Bombardieri R, Cerminara C. Current management for epilepsy in tuberous sclerosis complex. Curr Opin Neurol 2006; 19 (02) 119-123
- 174 Krueger D, Northrup H. TSC Clinical Consensus Conference Summary of Updates: Diagnosis, Treatment and Surveillance Guidelines. Silver Springs, MD: TSC; 2012
- 175 Wu JY, Peters JM, Goyal M. et al. Clinical electroencephalographic biomarker for impending epilepsy in asymptomatic tuberous sclerosis complex infants. Pediatr Neurol 2016; 54: 29-34
- 176 Chung CWT, Lawson JA, Sarkozy V. et al. Early detection of tuberous sclerosis complex: an opportunity for improved neurodevelopmental outcome. Pediatr Neurol 2017; 76: 20-26
- 177 Pitkänen A, Lukasiuk K. Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol 2011; 10 (02) 173-186
- 178 Domańska-Pakieła D, Kaczorowska M, Jurkiewicz E, Kotulska K, Dunin-Wąsowicz D, Jóźwiak S. EEG abnormalities preceding the epilepsy onset in tuberous sclerosis complex patients: a prospective study of 5 patients. Eur J Paediatr Neurol 2014; 18 (04) 458-468
- 179 Whitney R, Jan S, Zak M, McCoy B. The utility of surveillance electroencephalography to guide early antiepileptic drug therapy in infants with tuberous sclerosis complex. Pediatr Neurol 2017; 72: 76-80
- 180 The European Long-term, Prospective Study Evaluating Clinical and Molecular Biomarkers of Epileptogenesis in a Genetic Model of Epilepsy-Tuberous Sclerosis Complex (EPISTOP, clinicaltrials.gov NCT02098759). Accessed 2021 at: http://www.epistop.eu/images/EPISTOP
- 181 Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 2010; 51 (07) 1236-1241
- 182 Berg AT. Defining intractable epilepsy. Adv Neurol 2006; 97: 5-10
- 183 Curatolo P, Bombardieri R, Verdecchia M, Seri S. Intractable seizures in tuberous sclerosis complex: from molecular pathogenesis to the rationale for treatment. J Child Neurol 2005; 20 (04) 318-325
- 184 Yamamoto N, Watanabe K, Negoro T. et al. Long-term prognosis of tuberous sclerosis with epilepsy in children. Brain Dev 1987; 9 (03) 292-295
- 185 Koo B, Hwang PA, Logan WJ. Infantile spasms: outcome and prognostic factors of cryptogenic and symptomatic groups. Neurology 1993; 43 (11) 2322-2327
- 186 Wang YY, Pang LY, Ma SF, Zhang MN, Liu LY, Zou LP. Epilepsy may be the major risk factor of mental retardation in children with tuberous sclerosis: a retrospective cohort study. Epilepsy Behav 2017; 77: 13-18