Subscribe to RSS
DOI: 10.1055/s-0030-1269906
© Georg Thieme Verlag KG Stuttgart · New York
Tuberous Sclerosis Complex: Neurological, Renal and Pulmonary Manifestations
Publication History
received 24.11.2010
accepted 26.11.2010
Publication Date:
05 January 2011 (online)
Abstract
Tuberous sclerosis complex (TSC) is an important cause of epilepsy and autism, as well as renal and pulmonary disease in adults and children. Affected individuals are subject to hamartomas in various organ systems which result from constitutive activation of the protein kinase mTOR (mammalian target of rapamycin). The clinical course, prognosis and appropriate therapy for TSC patients are often different from that for individuals with epilepsy, renal tumors, or interstitial lung disease, from other causes. Additionally, TSC serves as a model for other conditions in which the mTOR pathways are also up-regulated. This article reviews the molecular pathophysiology and management of neurological, renal and pulmonary manifestations of the disorder. The use of mTOR inhibitors such as rapamycin and everolimus is discussed and recent clinical trials of these drugs in TSC are reviewed.
Key words
tuberous sclerosis - angiomyolipoma - epilepsy - lymphangioleiomyomatosis
References
- 1 Al-Saleem T. et al . Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer. 1998; 83 2208-2216
- 2 Augustine J, Bodziak K, Hricik D. Use of sirolimus in solid organ transplantation. Drugs. 2007; 67 369-391
- 3 Bernstein J, Meyer R. Parenchymal maldevelopment of the kidney.. in Brennemann-Kelley Practice of Pediatrics, V. KeHey, Editor. 1967. Harper: New York; 1-30
- 4 Bernstein J, Robbins TO. Renal involvement in tuberous sclerosis. Ann N Y Acad Sci. 1991; 615 36-49
- 5 Bernstein J. Glomerulocystic kidney disease – nosological considerations. Pediatr Nephrol. 1993; 7 464-470
- 6 Bernstein J. Renal cystic disease in the tuberous sclerosis complex. Pediatr Nephrol. 1993; 7 490-495
- 7 Bissler JJ. et al . Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008; 358 140-151
- 8 Bissler JJ, Siroky BJ, Yin H. Glomerulocystic kidney disease. Pediatr Nephrol. 2009; (in press)
- 9 Bolton P. et al . Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain. 2002; 125 1247-1255
- 10 Braffman B. et al . MR imaging of tuberous sclerosis: pathogenesis of this phakomatosis, use of gadopentetate dimeglumine, and literature review. Radiology. 1992; 183 227-238
- 11 Brook-Carter PT. et al . Deletion of the TSC2 and PKD1 genes associated with severe infantile polycystic kidney disease – a contiguous gene syndrome. Nature Genetics. 1994; 8 328-332
- 12 Buoni S. et al . Combined treatment with vigabatrin and topiramate in West syndrome. J Child Neurol. 2004; 19 385-386
- 13 Cao Y. et al . Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. J Biol Chem. 2006; 281 20483-20493
- 14 Carrington CB. et al . Lymphangioleiomyomatosis. Physiologic-pathologic-radiologic correlations. Am Rev Respir Dis. 1977; 116 977-995
- 15 Casper KA. et al . Tuberous sclerosis complex: renal imaging findings. Radiology. 2002; 225 451-456
- 16 Castro M. et al . Pulmonary tuberous sclerosis. Chest. 1995; 107 189-195
- 17 Chandra P. et al . FDG-PET/MRI coregistration and diffusion-tensor imaging distinguish epileptogenic tubers and cortex in patients with tuberous sclerosis complex: a preliminary report. Epilepsia. 2006; 47 1543-1549
- 18 Clarke A. et al . End-stage renal failure in adults with the tuberous sclerosis complex. Nephrol Dial Transpl. 1999; 14 988-991
- 19 Collins J. et al . Levetiracetam as adjunctive antiepileptic therapy for patients with tuberous sclerosis complex: a retrospective open-label trial. J Child Neurol. 2006; 21 53-57
- 20 Coppola G. et al . The effects of the ketogenic diet in refractory partial seizures with reference to tuberous sclerosis. Eur J Paediatr Neurol. 2006; 10 148-1451
- 21 Corrin B, Liebow AA, Friedman PJ. Pulmonary lymphangiomyomatosis. A review. Am J Pathology. 1975; 79 348-382
- 22 Crino P, Nathanson K, Henske E. The tuberous sclerosis complex. New Engl J Med. 2006; 355 1345-1356
- 23 Crooks DM. et al . Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis. Proc Natl Acad Sci USA. 2004; 101 17462-17467
- 24 Cuccia V. et al . Subependymal giant cell astrocytoma in children with tuberous sclerosis. Childs Nerv Sys. 2003; 19 232-243
- 25 Curatolo P, Verdecchia M, Bombardieri R. Tuberous sclerosis complex: a review of neurological aspects. Europ J Paediatr Neurol. 2002; 6 15-23
- 26 Curatolo P. Tuberous Sclerosis Complex: From Basic Science to Clinic Phenotypes. International Review of Child Neurology Series 2003: Mac Keith Press
- 27 Dabora SL. 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 64-80
- 28 Davies DM. et al . Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis. N Engl J Med. 2008; 358 200-203
- 29 Eble JN, Hull MT. Morphologic features of renal oncocytoma: a light and electron microscopic study. Hum Pathol. 1984; 15 1054-1061
- 30 Eble JN, Amin MB, Young RH. Epithelioid angiomyolipoma of the kidney: a report of five cases with a prominent and diagnostically confusing epithelioid smooth muscle component. Am J Surg Pathol. 1997; 21 1123-1130
- 31 Ehninger D. et al . Reversal of learning deficits in a Tsc2±mouse model of tuberous sclerosis. Nature Medicine. 2008; 14 843-848
- 32 European Chromosome 16 Tuberous Sclerosis Consortium . Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell. 1993; 75 1305-1315
- 33 Ferrans VJ. et al . Lymphangioleiomyomatosis (LAM): a review of clinical and morphological features. J Nippon Med Sch. 2000; 67 311-329
- 34 Ferry JA, Malt RA, Young RH. Renal angiomyolipoma with sarcomatous transformation and pulmonary metastases. Am J Surg Pathol. 1991; 15 1083-1088
- 35 Folpe AL. et al . Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol. 2005; 29 1558-1575
- 36 Fox CH. et al . A quick guide to evidence-based chronic kidney disease care for the primary care physician. Postgrad Med. 2008; 120 E01-E06
- 37 Franz D. 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; 164 661-668
- 38 Franz D, Tudor C, Leonard J. Topiramate as therapy for tuberous sclerosis complex-associated seizures. Epilepsia. 2000; 41 (S 07) 87
- 39 Franz DN. et al . Lamotrigine therapy of epilepsy in tuberous sclerosis. Epilepsia. 2001; 42 935-940
- 40 Franz DN. et al . Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol. 2006; 59 490-498
- 41 Franz DN. unpublished observations
- 42 Goh S. et al . Infantile spasms and intellectual outcomes in children with tuberous sclerosis complex. Neurology. 2005; 65 235-238
- 43 Goh S. Subependymal giant cell tumors in tuberous sclerosis complex. Neurology. 2004; 63 1457-1461
- 44 Gong R. et al . Roles of glutamate receptors and the mammalian target of rapamycin (mTOR) signaling pathway in activity-dependent dendritic protein synthesis in hippocampal neurons. J Biol Chem. 2006; 281 18802-18815
- 45 Hancock E, Osborne J. Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review. J Child Neurol. 1999; 14 71-74
- 46 Henske EP. Metastasis of benign tumor cells in tuberous sclerosis complex. Genes Chromosomes Cancer. 2003; 38 376-381
- 47 Henske EP. Tuberous sclerosis and the kidney: from mesenchyme to epithelium, and beyond. Pediatr Nephrol. 2005; 20 854-857
- 48 Hyman M, Whittemore V. National Institutes of Health consensus conference: tuberous sclerosis complex. Arch Neurol. 2000; 57 662-665
- 49 Inoki K, Guan K. Complexity of the TOR signaling network. Trends Cell Biol. 2006; 16 206-212
- 50 Jambaqué I. et al . Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patients. Epilepsy Res. 2000; 38 151-160
- 51 Jansen F. et al . Epilepsy surgery in tuberous sclerosis: a systematic review. Epilepsia. 2007; 48 1466-1484
- 52 Jaworski J, Sheng M. The growing role of mTOR in neuronal development and plasticity. Mol Neurobiol. 2006; 34 205-219
- 53 Jimenez RE. et al . Concurrent angiomyolipoma and renal cell neoplasia: a study of 36 cases. Mod Pathol. 2001; 14 157-163
- 54 Joinson C. et al . Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychol Med. 2003; 33 335-344
- 55 Jozwiak S, Goodman M, Lamm S. Poor mental development in patients with tuberous sclerosis complex: clinical risk factors. Arch Neurol. 1998; 55 379-384
- 56 Karbowniczek M. et al . Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism. Am J Respir Crit Care Med. 2003; 167 976-982
- 57 Karbowniczek M, Yu MJ, Henske EP. Renal angiomyolipomas from patients with sporadic lymphangiomyomatosis contain both neoplastic and non-neoplastic vascular structures. Am J Pathol. 2003; 162 491-500
- 58 Kennelly MJ, Grossman HB, Cho KJ. Outcome analysis of 42 cases of renal angiomyolipoma [see comments]. J Urol. 1994; 152 1988-1991
- 59 Kessler OJ. et al . Management of renal angiomyolipoma: analysis of 15 cases. Eur Urol. 1998; 33 572-575
- 60 Kitaichi M. et al . Pulmonary lymphangioleiomyomatosis: a report of 46 patients including a clinicopathologic study of prognostic factors. Am J Respir Crit Care Med. 1995; 151 527-533
- 61 Kossoff E. et al . A modified Atkins diet is effective for the treatment of intractable pediatric epilepsy. Epilepsia. 2006; 47 421-424
- 62 Kossoff E. et al . Tuberous sclerosis complex and the ketogenic diet. Epilepsia. 2005; 46 1684-1686
- 63 Koyama M. et al . Chronic cystic lung disease: diagnostic accuracy of high-resolution CT in 92 patients. Am J Roentgenol. 2003; 180 827-835
- 64 Krueger D. et al . Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. New Engl J Med. 2010; 363 1801-1811
- 65 Kumasaka T. et al . Lymphangiogenesis-mediated shedding of LAM cell clusters as a mechanism for dissemination in lymphangioleiomyomatosis. Am J Surg Pathol. 2005; 29 1356-1366
- 66 Lamb E, Stevens P, Nashef L. Topiramate increases biochemical risk of nephrolithiasis. Ann Clin Biochem. 2004; 41 166-169
- 67 Lane BR. et al . Clinical correlates of renal angiomyolipoma subtypes in 209 patients: classic, fat poor, tuberous sclerosis associated and epithelioid. J Urol. 2008; 180 836-843
- 68 Lawden M. et al . Visual field defects associated with vigabatrin therapy. J Neurol Neurosurg Psychiatry. 1999; 67 716-722
- 69 Lemaitre L. et al . Renal angiomyolipoma: growth followed up with CT and/or US [see comments]. Radiology. 1995; 197 598-602
- 70 Lenz G, Avruch J. Glutamatergic regulation of the p70S6 kinase in primary mouse neurons. J Biol Chem. 2005; 280 38121-38124
- 71 Levine N. et al . Gradual formation of an operative corridor by balloon dilation for resection of subependymal giant cell astrocytomas in children with tuberous sclerosis: specialized minimal access technique of balloon dilation. Minim Invas Neurosurg. 2006; 49 317-320
- 72 Ma L. et al . Identification of S664 TSC2 phosphorylation as a marker for Erk-mediated mTOR activation in tuberous sclerosis and human cancer. Cancer Res. 2007; 67 7106-7112
- 73 Madhavan D. et al . Surgical outcome in tuberous sclerosis complex: a multicenter survey. Epilepsia. 2007; 48 1625-1628
- 74 Mai KT, Perkins DG, Collins JP. Epithelioid cell variant of renal angiomyolipoma [see comments]. Histopathology. 1996; 28 277-280
- 75 Manuchehri K. et al . A controlled study of vigabatrin and visual abnormalities. Br J Ophthalmol. 2000; 84 499-505
- 76 McCormack FX, Moss J. S-LAM in a man?. Am J Respir Crit Care Med. 2007; 176 3-5
- 77 McCormack FX. Lymphangioleiomyomatosis: a clinical update. Chest. 2008; 133 507-516
- 78 McCullough DL, Scott Jr R, Seybold HM. Renal angiomyolipoma (hamartoma): review of the literature and report of 7 cases. J Urol. 1971; 105 32-44
- 79 Meikle L. et al . Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci. 2008; 28 5422-5432
- 80 Moss J. et al . Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med. 2001; 164 669-671
- 81 Muir TE. et al . Micronodular pneumocyte hyperplasia. Am J Surg Pathol. 1998; 22 465-472
- 82 Muller NL, Chiles C, Kullnig P. Pulmonary lymphangiomyomatosis: correlation of CT with radiographic and functional findings. Radiology. 1990; 175 335-339
- 83 Muncy J, Butler IJ, Koenig MK. Rapamycin reduces seizure frequency in tuberous sclerosis complex. J Child Neurol. 2009; 24 477
- 84 Obuz F. et al . Various radiological appearances of angiomyolipomas in the same kidney. Eur Radiol. 2000; 10 897-899
- 85 Ou YC. et al . Renal angiomyolipoma: experience of 23 patients. Chung Hua i Hsueh Tsa Chih - Chin Med J. 1991; 48 217-223
- 86 Paccalin M. et al . Activated mTOR and PKR kinases in lymphocytes correlate with memory and cognitive decline in Alzheimer's disease. Dementia and geriatric cognitive disorders. 2006; 22 320-326
- 87 Pea M. et al . Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma. Am J Surg Pathol. 1998; 22 180-187
- 88 Pellock J. et al . Felbamate: consensus of current clinical experience. Epilepsy Res. 2006; 71 89-101
- 89 Peng T, Golub TR, Sabatini DM. The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation. Mol Cell Biol. 2002; 22 5575-5584
- 90 Pfeifer H, Thiele E. Low-glycemic-index treatment: a liberalized ketogenic diet for treatment of intractable epilepsy. Neurology. 2005; 65 1810-1812
- 91 Prather P, de Vries P. Behavioral and cognitive aspects of tuberous sclerosis complex. J Child Neurol. 2004; 19 666-674
- 92 Pulsifer M, Winterkorn E, Thiele E. Psychological profile of adults with tuberous sclerosis complex. Epilepsy Behav. 2007; 10 402-406
- 93 Raab-Graham K. et al . Activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites. Science. 2006; 314 144-148
- 94 Rakowski SK. et al . Renal manifestations of tuberous sclerosis complex: Incidence, prognosis, and predictive factors. Kidney Int. 2006; 70 1777-1782
- 95 Ravikumar B. et al . Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genetics. 2004; 36 585-595
- 96 Rowley S, O’Callaghan F, Osborne J. Ophthalmic manifestations of tuberous sclerosis: a population based study. Br J Ophthalmol. 2001; 85 420-423
- 97 Ryu JH. et al . The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med. 2006; 173 105-111
- 98 Saito K. et al . Malignant clear cell “sugar” tumor of the kidney: clear cell variant of epithelioid angiomyolipoma. J Urol. 2002; 168 2533-2534
- 99 Sampson JR. et al . Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene. Am J Hum Genet. 1997; 61 843-851
- 100 Sarnat HB, Flores-Sarnat L. Embryology of the neural crest: its inductive role in the neurocutaneous syndromes. J Child Neurol. 2005; 20 637-643
- 101 Schillinger F, Montagnac R. Chronic renal failure and its treatment in tuberous sclerosis. Nephrol Dial Transpl. 1996; 11 481-485
- 102 Sehgal S, Baker H, Vézina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot. 1975; 28 727-732
- 103 Seyama K. et al . Vascular endothelial growth factor-D is increased in serum of patients with lymphangioleiomyomatosis. Lymphat Res Biol. 2006; 4 143-152
- 104 Shepherd CW. et al . Causes of death in patients with tuberous sclerosis. Mayo Clin Proceed. 1991; 66 792-796
- 105 Steiner MS. et al . The natural history of renal angiomyolipoma. J Urol. 1993; 150 1782-1786
- 106 Stillwell TJ, Gomez MR, Kelalis PP. Renal lesions in tuberous sclerosis. J Urol. 1987; 138 477-481
- 107 Takayanagi M. et al . Two successful cases of bromide therapy for refractory symptomatic localization-related epilepsy. Brain Develop. 2002; 24 194-196
- 108 Tavazoie S. et al . Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nature Neuroscience. 2005; 8 1727-1734
- 109 Taveira-DaSilva A. et al . Reversible airflow obstruction, proliferation of abnormal smooth muscle cells, and impairment of gas exchange as predictors of outcome in lymphangioleiomyomatosis. Am J Respir Crit Care Med. 2001; 164 1072-1076
- 110 Thiele E. Managing epilepsy in tuberous sclerosis complex. J Child Neurol. 2004; 19 680-686
- 111 Tillema J, Franz D. Data on file in manuscript (in press)
- 112 van Slegtenhorst M. et al . Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997; 277 805-808
- 113 Verrotti A. et al . Antiepileptic drugs and visual function. J Pediatr Neurol. 2007; 36 353-360
- 114 Vicente MP, Pons M, Medina M. Pulmonary involvement in tuberous sclerosis. Pediatr Pulmonol. 2004; 37 178-180
- 115 von der Brelie C. et al . Impaired synaptic plasticity in a rat model of tuberous sclerosis. Eur J Neurosci. 2006; 23 686-692
- 116 Wang Y, Barbaro M, Baraban S. A role for the mTOR pathway in surface expression of AMPA receptors. Neurosci Lett. 2006; 401 35-39
- 117 Winterkorn EB, Pulsifer M, Thiele E. Cognitive prognosis of patients with tuberous sclerosis complex. Neurology. 2007; 68 62-64
- 118 Wong M. Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies. Epilepsia. 2009; 51 27-36
- 119 Xu L. et al . Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain. FEBS J. 2005; 272 4211-4220
- 120 Yamakado K. et al . Renal angiomyolipoma: relationships between tumor size, aneurysm formation, and rupture. Radiology. 2002; 225 78-82
- 121 Yates J. Tuberous sclerosis. Eur J Hum Genet. 2006; 14 1065-1073
- 122 Young LR, Inoue Y, McCormack FX. Diagnostic potential of serum VEGF-D for lymphangioleiomyomatosis. N Engl J Med. 2008; 358 199-200
- 123 Zeng LH. et al . Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol. 2008; 63 444-453
- 124 Zeng LH, Rensing NR, Wong M. The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J Neurosci. 2009; 29 6964-6972
- 125 Zhang Y. et al . Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nature Cell. 2003; 5 578-581
Correspondence
David Neal FranzMD
Children's Hospital Medical
Center
Neurology / MLC 2015
3333 Burnet Avenue
Cincinnati
45229 Ohio
USA
Phone: +1/513/636 4762
Fax: +1/513/636 1888
Email: franz@tsdev.org