Correspondence
The Tuberous Sclerosis Complex
N Engl J Med 2007; 356:92-94January 4, 2007
- Article
To the Editor:
We wish to reframe the discussion regarding the neurodevelopmental manifestations of the tuberous sclerosis complex (TSC) in the overview of TSC by Crino et al. (Sept. 28 issue).1 First, the authors state, “Epilepsy may be the most prevalent and challenging clinical manifestation of TSC.” However, patients and caregivers have reported that cognitive and behavioral difficulties are the greatest challenge, over and above epilepsy,2 and they continue to do so. Almost everyone with TSC, even in the absence of epilepsy, has clinically significant cognitive or behavioral problems.3
Second, the authors state that the neurobehavioral abnormalities “appear to be intimately related to the cerebral cortical tubers” and that “the number of tubers may also be an independent risk factor for cognitive disability.” Data show associations, but no data show a causal role of tubers in intellectual disability.1,3 Tubers and infantile spasms explain less than 50% of the IQ variance among patients with TSC.4 TSC has at least two distinct cognitive endophenotypes3 (Figure 1Figure 1
Two Cognitive Endophenotypes in TSC.),5 probably with different etiologic mechanisms. We would argue that tubers and seizures are neither necessary nor sufficient to explain the neuropsychiatric manifestations of TSC and that molecular hypotheses and experimental evidence are required.5 ReferencesPetrus J. de Vries, M.B., Ch.B., Ph.D.
University of Cambridge, Cambridge CB2 2AH, United Kingdom
pd215@cam.ac. uk Penny A. Prather, Ph.D.
Boston University School of Medicine, Boston, MA 024591
Crino PB ,Nathanson KL ,Henske EP . The tuberous sclerosis complex. N Engl J Med 2006;355:1345-1356
Full Text | Web of Science | Medline2
Hunt A . Tuberous sclerosis: a survey of 97 cases. III: Family aspects. Dev Med Child Neurol 1983;25:353-357
CrossRef | Web of Science | Medline3
Prather P ,de Vries PJ . Behavioral and cognitive aspects of tuberous sclerosis complex. J Child Neurol 2004;19:666-674
Web of Science | Medline4
O'Callaghan FJK ,Harris T ,Joinson C , et al. The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Arch Dis Child 2004;89:530-533
CrossRef | Web of Science | Medline5
Joinson C ,O'Callaghan FJ ,Osborne JP ,Martyn C ,Harris T ,Bolton PF . Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis. Psychol Med 2003;33:335-344
CrossRef | Web of Science | Medline
To the Editor:
Crino et al. recommend annual magnetic resonance imaging (MRI) of the brain until patients are at least 21 years of age and then every 2 to 3 years. Are there any evidence-based guidelines that provide support for this recommendation? I wonder whether brain MRI changes the care of these patients. Are asymptomatic patients referred to the neurosurgeon for prophylactic surgery? If not, would it not be less anxiety provoking and surely much less expensive to follow them with an annual, thorough neurologic examination?
Dan Lipsker, M.D.
Université Louis Pasteur, 67000 Strasbourg, France
dlipsker@noos.fr To the Editor:
Crino and colleagues discuss the pathogenesis of TSC but they do not refer to the role of tuberin (TSC2) in the regulation of the endocytic machinery, which is important in the pathogenesis of TSC. TSC belongs to a group of disorders that include other neurodegenerative diseases such as X-linked mental retardation (Rab–GDIa defects) and Charcot–Marie–Tooth type 2B disease (rab7 mutations). These diseases share an impairment in intracellular transport machinery due to an alteration in the function or regulation of Rab GTPases.1,2 Rab GTPases control vesicular membrane transport on exocytic and endocytic pathways. TSC2 is a GTPase-activating protein (GAP) for Rab5 GTPase and exerts its GAP function toward Rab5 through rabaptin-5.3 Loss of TSC2–GAP activity results in failure to stimulate Rab5–GTP hydrolysis and failure to release Rab5 GDP and rabaptin-5 into the cytosol for recycling; this interferes with docking, fusion, and processing of Rab5 GTP–associated endosomes. The development of polycystic kidney disease (PKD) in TSC is consistent with this mechanism. The loss of TSC2 function disrupts vesicular transport of polycystin-1 (the PKD1 gene product), resulting in its sequestration within the Golgi and conferring a predisposition to PKD.4
4 ReferencesPanagiotis A. Konstantinopoulos, M.D., Ph.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215
pkonstan@bidmc.harvard. edu Athanasios G. Papavassiliou, M.D., Ph.D.
University of Athens Medical School, 11527 Athens, Greece1
D'Adamo P ,Menegon A ,Lo Nigro C , et al. Mutations in GDI1 are responsible for X-linked non-specific mental retardation. Nat Genet 1998;19:134-139[Erratum, Nat Genet 1998;19:303.]
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Verhoeven K ,De Jonghe P ,Coen K , et al. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am J Hum Genet 2003;72:722-727
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Xiao GH ,Shoarinejad F ,Jin F ,Golemis EA ,Yeung RS . The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. J Biol Chem 1997;272:6097-6100
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Kleymenova E ,Ibraghimov-Beskrovnaya O ,Kugoh H , et al. Tuberin-dependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene. Mol Cell 2001;7:823-832
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Author/Editor Response
We agree with de Vries and Prather that neurobehavioral issues are important in many people with TSC. However, practical clinical experience shows that a considerable number of patients with TSC have no neurobehavioral abnormalities. The treatment of intractable epilepsy in patients with TSC is associated with sobering complications that are distinct from those associated with cognitive or behavioral therapies. The combined and often life-threatening illnesses resulting from multiple trials of antiepileptic drugs, intracranial electroencephalographic monitoring, and subsequent epilepsy surgery include toxic-drug reactions, infection, hemorrhage, and status epilepticus. These conditions make the treatment of epilepsy in TSC a particularly daunting challenge.
De Vries and Prather make the valid point that a “causal role” of tubers in diminished intellectual disability has not been established. For example, in a recent cohort of 25 high-functioning patients with TSC, there was no correlation between whole-brain tuber volume and IQ, but there was a significant relationship between tuber volume and the presence or absence of epilepsy.1 However, de Vries and Prather cite the work of O'Callaghan et al., who conclude that both the number of cortical tubers and the presence or absence of a history of infantile spasms affect IQ in patients with TSC.2 The relationship may be complex and may include other phenotypic features, such as the effects of bilateral tubers or the effect of tubers in a particular brain lobe. Microscopic regions of an abnormal brain structure that are below the resolution of radiographic detection may contribute to cognitive disability. Recent work suggests that subtle changes in dendritic spine morphology in in vitro TSC models are functionally important.3
The issue of MRI as a surveillance tool in subependymal giant-cell tumors was addressed in a cohort of 134 patients with TSC.4 The authors concluded that annual screening with brain MRI was prudent. The neurologic examination may not be sensitive enough to detect enlarging lesions that can lead to hydrocephalus and become acutely symptomatic.
Konstantinopoulos and Papavassiliou are correct that aberrant protein transport has been consistently observed in cellular models of TSC. However, whether these changes depend on Rab5, as originally proposed, rather than Rheb–mTOR, is an area of ongoing investigation.5
5 ReferencesPeter B. Crino, M.D., Ph.D.
Katherine L. Nathanson, M.D.
University of Pennsylvania Medical Center, Philadelphia, PA 19104
peter.crino@uphs. upenn. edu Elizabeth Petri Henske, M.D.
Fox Chase Cancer Center, Philadelphia, PA 191111
Ridler K ,Suckling J ,Higgins N ,Bolton P ,Bullmore E . Standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex. J Child Neurol 2004;19:658-665
Web of Science | Medline2
O'Callaghan FJK ,Harris T ,Joinson C , et al. The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Arch Dis Child 2004;89:530-533
CrossRef | Web of Science | Medline3
Tavazoie SF ,Alvarez VA ,Ridenour DA ,Kwiatkowski DJ ,Sabatini BL . Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci 2005;8:1727-1734
CrossRef | Web of Science | Medline4
Goh S ,Butler W ,Thiele EA . Subependymal giant cell tumors in tuberous sclerosis complex. Neurology 2004;63:1457-1461
Web of Science | Medline5
Jiang X ,Yeung RS . Regulation of microtubule-dependent protein transport by the TSC2/mammalian target of rapamycin pathway. Cancer Res 2006;66:5258-5269
CrossRef | Web of Science | Medline
- Citing Articles (16)
Citing Articles
1
Janani Kassiri, Thomas J. Snyder, Ravi Bhargava, B. Matt Wheatley, D. Barry Sinclair. (2011) Cortical Tubers, Cognition, and Epilepsy in Tuberous Sclerosis. Pediatric Neurology 44:5, 328-332
CrossRef2
Dan Ehninger, Alcino J. Silva. (2011) Increased Levels of Anxiety-related Behaviors in a Tsc2 Dominant Negative Transgenic Mouse Model of Tuberous Sclerosis. Behavior Genetics 41:3, 357-363
CrossRef3
Robert Waltereit, Birte Japs, Miriam Schneider, Petrus J. Vries, Dusan Bartsch. (2011) Epilepsy and Tsc2 Haploinsufficiency Lead to Autistic-Like Social Deficit Behaviors in Rats. Behavior Genetics 41:3, 364-372
CrossRef4
Kevin M. Tierney, Deborah L. McCartney, Jaco R. Serfontein, Petrus J. Vries. (2011) Neuropsychological Attention Skills and Related Behaviours in Adults with Tuberous Sclerosis Complex. Behavior Genetics 41:3, 437-444
CrossRef5
Dan Ehninger, Alcino J. Silva. (2011) Rapamycin for treating Tuberous sclerosis and Autism spectrum disorders. Trends in Molecular Medicine 17:2, 78-87
CrossRef6
Petrus J. Vries. (2010) Targeted treatments for cognitive and neurodevelopmental disorders in tuberous sclerosis complex. Neurotherapeutics 7:3, 275-282
CrossRef7
H. P. P. Gama, A. J. da Rocha, R. M. F. Valerio, C. J. da Silva, L. A. L. Garcia. (2010) Hippocampal Abnormalities in an MR Imaging Series of Patients with Tuberous Sclerosis. American Journal of Neuroradiology 31:6, 1059-1062
CrossRef8
Petrus J. de Vries. 2010. Neurodevelopmental, Psychiatric and Cognitive Aspects of Tuberous Sclerosis Complex. , 229-267.
CrossRef9
D. Ehninger, P. J. de Vries, A. J. Silva. (2009) From mTOR to cognition: molecular and cellular mechanisms of cognitive impairments in tuberous sclerosis. Journal of Intellectual Disability Research 53:10, 838-851
CrossRef10
Kevin C. Ess. (2009) Tuberous sclerosis complex: everything old is new again. Journal of Neurodevelopmental Disorders 1:2, 141-149
CrossRef11
Petrus J. de Vries, Julian Gardiner, Patrick F. Bolton. (2009) Neuropsychological attention deficits in tuberous sclerosis complex (TSC). American Journal of Medical Genetics Part A 149A:3, 387-395
CrossRef12
Dan Ehninger, Sangyeul Han, Carrie Shilyansky, Yu Zhou, Weidong Li, David J Kwiatkowski, Vijaya Ramesh, Alcino J Silva. (2008) Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nature Medicine 14:8, 843-848
CrossRef13
P. J. de Vries, P. Watson. (2008) Attention deficits in tuberous sclerosis complex (TSC): rethinking the pathways to the endstate. Journal of Intellectual Disability Research 52:4, 348-357
CrossRef14
Susanna M. I. Goorden, Geeske M. van Woerden, Louise van der Weerd, Jeremy P. Cheadle, Ype Elgersma. (2007) Cognitive deficits in Tsc1 +/− mice in the absence of cerebral lesions and seizures. Annals of Neurology 62:6, 648-655
CrossRef15
Petrus J. de Vries, Christopher J. Howe. (2007) The tuberous sclerosis complex proteins – a GRIPP on cognition and neurodevelopment. Trends in Molecular Medicine 13:8, 319-326
CrossRef16
M V Karamouzis, P A Konstantinopoulos, A G Papavassiliou. (2007) Compartmentalisation of EGFR signalling might potentiate the optimal use of EGFR tyrosine kinase inhibitors in cancer therapeutics. British Journal of Cancer 96:12, 1924-1925
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