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. 2010 Jul;7(3):275–282. doi: 10.1016/j.nurt.2010.05.001

Targeted treatments for cognitive and neurodevelopmental disorders in tuberous sclerosis complex

Petrus J de Vries 1,✉
PMCID: PMC5084231  PMID: 20643380

Summary

Until recently, the neuropsychiatric phenotype of tuberous sclerosis complex (TSC) was presumed to be caused by the structural brain abnormalities and/or seizures seen in the disorder. However, advances in the molecular biology of the disorder have shown that TSC is a mammalian target of rapamycin (mTOR) overactivation syndrome, and that direct molecular pathways exist between gene mutation and cognitive/neurodevelopmental phenotype. Molecularly-targeted treatments using mTOR inhibitors (such as rapamycin) are showing great promise for the physical and neurological phenotype of TSC. Pre-clinical and early-phase clinical studies of the cognitive and neurodevelopmental features of TSC suggest that some of the neuropsychiatric phenotypes might also be reversible, even in adults with the disorder. TSC, fragile X, neurofibromatosis type 1, and disorders associated with phosphatase and tensin homo (PTEN) mutations, all signal through the mTOR signaling pathway, with the TSC1-TSC2 protein complex as a molecular switchboard at its center. Together, these disorders represent as much as 14% of autism spectrum disorders (ASD). Therefore, we suggest that this signaling pathway is a key to the underlying pathophysiology of a significant subset of individuals with ASD. The study of molecularly targeted treatments in TSC and related disorders, therefore, may be of scientific and clinical value not only to those with TSC, but to a larger population that may have a neuropsychiatric phenotype attributable to mTOR overactivation or dysregulation.

Key Words: TSC, mTOR, rapamycin, neurocognition, memory, autism, autism spectrum disorders

References

  • 1.Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med. 2006;355:1345–1356. doi: 10.1056/NEJMra055323. [DOI] [PubMed] [Google Scholar]
  • 2.de Vries PJ, Howe CJ. The tuberous sclerosis complex proteins—a GRIPP on cognition and neurodevelopment. Trends Mol Med. 2007;13:319–326. doi: 10.1016/j.molmed.2007.06.003. [DOI] [PubMed] [Google Scholar]
  • 3.Jones AC. Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum Mol Genet. 1997;6:2155–2161. doi: 10.1093/hmg/6.12.2155. [DOI] [PubMed] [Google Scholar]
  • 4.Dabora SL. 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. doi: 10.1086/316951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Roach ES, Gomez MR, Northrup H. Tuberous sclerosis consensus conference: revised diagnostic criteria. J Child Neurol. 1998;13:624–628. doi: 10.1177/088307389801301206. [DOI] [PubMed] [Google Scholar]
  • 6.Ridler K. Neuroanatomical correlates of memory deficits in tuberous sclerosis complex. Cereb Cortex. 2007;17:261–271. doi: 10.1093/cercor/bhj144. [DOI] [PubMed] [Google Scholar]
  • 7.Ridler K. Widespread anatomical abnormalities of grey and white matter structure in tuberous sclerosis. Psychol Med. 2001;31:1437–1446. doi: 10.1017/S0033291701004561. [DOI] [PubMed] [Google Scholar]
  • 8.Franz DN, de Vries PJ, Crino PB. Giant cell astrocytomas in tuberous sclerosis complex. Arch Dis Child. 2009;94:75–76. [PubMed] [Google Scholar]
  • 9.Franz DN, Leonard J, Tudor C, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol. 2006;59:490–498. doi: 10.1002/ana.20784. [DOI] [PubMed] [Google Scholar]
  • 10.Wong M. Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: from tuberous sclerosis to common acquired epilepsies. Epilepsia. 2010;51:27–36. doi: 10.1111/j.1528-1167.2009.02341.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Ehninger D, de Vries PJ, Silva AJ. From mTOR to cognition: molecular and cellular mechanisms of cognitive impairment in tuberous sclerosis. J Intellect Disabil Res. 2009;53:838–851. doi: 10.1111/j.1365-2788.2009.01208.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Prather P, de Vries PJ. Behavioral and cognitive aspects of tuberous sclerosis complex. J Child Neurol. 2004;19:666–674. doi: 10.1177/08830738040190090601. [DOI] [PubMed] [Google Scholar]
  • 13.Joinson C. Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychol Med. 2003;33:335–344. doi: 10.1017/S0033291702007092. [DOI] [PubMed] [Google Scholar]
  • 14.de Vries PJ, Prather P. The tuberous sclerosis complex. N Engl J Med. 2007;356:92–92. doi: 10.1056/NEJMc062928. [DOI] [PubMed] [Google Scholar]
  • 15.Bolton PF, Park RJ, Higgins NP, Griffiths PD, Pickles A. Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain. 2002;125:1247–1255. doi: 10.1093/brain/awf124. [DOI] [PubMed] [Google Scholar]
  • 16.Kelleher RJ, Bear MF. The autistic neuron: troubled translation? Cell. 2008;135:401–406. doi: 10.1016/j.cell.2008.10.017. [DOI] [PubMed] [Google Scholar]
  • 17.de Vries PJ, Hunt A, Bolton PF. The psychopathologies of children and adolescents with tuberous sclerosis complex (TSC): a postal survey of UK families. Eur Child Adolesc Psychiatry. 2006;16:16–24. doi: 10.1007/s00787-006-0570-3. [DOI] [PubMed] [Google Scholar]
  • 18.Lewis JC, Thomas HV, Murphy KC, Sampson JR. Genotype and psychological phenotype in tuberous sclerosis. J Med Genet. 2004;41:203–207. doi: 10.1136/jmg.2003.012757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Smalley SL, Burger F, Smith M. Phenotypic variation of tuberous sclerosis in a single extended kindred. J Med Genet. 1994;31:761–765. doi: 10.1136/jmg.31.10.761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.de Vries PJ, Gardiner J, Bolton PF. Neuropsychological attention deficits in tuberous sclerosis complex (TSC) Am J Med Genet Part A. 2009;149A:387–395. doi: 10.1002/ajmg.a.32690. [DOI] [PubMed] [Google Scholar]
  • 21.McCartney DL, Bullmore ET, Suckling J, et al. Lateralised spatial attentional bias and white matter tract connectivity in tuberous sclerosis complex (TSC) J Intell Disabil Res. 2009;53:836–836. [Google Scholar]
  • 22.Sahakian BJ, Owen AM. Computerized assessment in neuropsychiatry using CANTAB: discussion paper. J Royal Soc Med. 1992;85:399–402. [PMC free article] [PubMed] [Google Scholar]
  • 23.Kwiatkowski DJ, Manning BD. Tuberous sclerosis: a GAP at the crossroads of multiple signalling pathways. Hum Mol Genet. 2005;14:R251–R258. doi: 10.1093/hmg/ddi260. [DOI] [PubMed] [Google Scholar]
  • 24.Sampson JR. Therapeutic targeting of mTOR in tuberous sclerosis. Biochem Soc Trans. 2009;37:259–264. doi: 10.1042/BST0370259. [DOI] [PubMed] [Google Scholar]
  • 25.Jacinto ER, Loewith A, Schmidt S, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biol. 2004;6:1122–1128. doi: 10.1038/ncb1183. [DOI] [PubMed] [Google Scholar]
  • 26.Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30:214–226. doi: 10.1016/j.molcel.2008.03.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Serfontein J, Nisbet RER, Howe CJ, de Vries PJ. Evolution of the TSC1/TSC2-TOR signalling pathway. Sci Signal. 2010;3:ra49–ra49. doi: 10.1126/scisignal.2000803. [DOI] [PubMed] [Google Scholar]
  • 28.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. doi: 10.1136/adc.2003.026815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Raznahan A, Higgins NP, Griffiths PD, Humphrey A, Yates JRW, Bolton PF. Biological markers of intellectual disability in tuberous sclerosis. Psychol Med. 2007;37:1293–1304. doi: 10.1017/S0033291707000177. [DOI] [PubMed] [Google Scholar]
  • 30.Jozwiak S, Domanska-Pakiela D, Kotulska K, et al. New indications for antiepileptic drugs application in infants with tuberous sclerosis complex — prevention of epilepsy. Pharmacol Reports. 2009;61:580–581. [Google Scholar]
  • 31.Costa-Mattioli M, Sossin WS, Klann E, Sonenberg N. Translational control of long-lasting synaptic plasticity and memory. Neuron. 2009;61:10–26. doi: 10.1016/j.neuron.2008.10.055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Goorden SMI, van Woerden GM, van der Weerd L, Cheadle JP, Elgersma Y. Cognitive deficits in Tsc1+/− mice in the absence of cerebral lesions and seizures. Ann Neurol. 2007;62:648–655. doi: 10.1002/ana.21317. [DOI] [PubMed] [Google Scholar]
  • 33.Ehninger D, Han S, Shilyansky C, et al. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat Med. 2008;14:843–848. doi: 10.1038/nm1788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Mozzaffari 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;10:88–88. doi: 10.1186/1471-2350-10-88. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Nellist M, Sancak O, Goedbloed MA, et al. Distinct effects of single amino-acid changes to tuberin on the function of the tuberinhamartin complex. Eur J Hum Genet. 2005;13:59–68. doi: 10.1038/sj.ejhg.5201276. [DOI] [PubMed] [Google Scholar]
  • 36.Persico AM, Bourgeron T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci. 2006;29:349–358. doi: 10.1016/j.tins.2006.05.010. [DOI] [PubMed] [Google Scholar]
  • 37.de Vries PJ. Genetics and neuropsychiatric disorders: genomewide, yet narrow. Nat Med. 2009;15:850–851. doi: 10.1038/nm0809-850. [DOI] [PubMed] [Google Scholar]
  • 38.Wang LW, Berry-Kravis E, Hagerman RJ. Fragile X: leading the way for targeted treatments in autism. Neurotherapeutics. 2010;7:264–274. doi: 10.1016/j.nurt.2010.05.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Kwon CH, Luikart BW, Powell CM, et al. PTEN regulates neuronal arborisation and social interaction in mice. Neuron. 2006;50:377–388. doi: 10.1016/j.neuron.2006.03.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Johannessen CM, Reczek EE, James MF, Brems H, Legius E, Cichowski K. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci USA. 2005;102:8573–8578. doi: 10.1073/pnas.0503224102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Kenerson H, Dundon TA, Yeung RS. Effects of rapamycin in the Eker rat model of tuberous sclerosis complex. Pediatr Res. 2005;57:67–75. doi: 10.1203/01.PDR.0000147727.78571.07. [DOI] [PubMed] [Google Scholar]
  • 42.Lee L, Sudentas P, Donohue B, et al. Efficacy of a rapamycin analog (CCI-779) and IFN-γ in tuberous sclerosis mouse models. Genes Chromosomes Cancer. 2005;42:213–227. doi: 10.1002/gcc.20118. [DOI] [PubMed] [Google Scholar]
  • 43.Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008;358:140–151. doi: 10.1056/NEJMoa063564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Davies DM, Johnson SR, Tattersfield AE, et al. Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis. N Engl J Med. 2008;358:200–203. doi: 10.1056/NEJMc072500. [DOI] [PubMed] [Google Scholar]
  • 45.Hofbauer GFL, Marcollo-Pini A, Corsenca A, et al. The mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis. B J Dermatol. 2008;159:473–475. doi: 10.1111/j.1365-2133.2008.08677.x. [DOI] [PubMed] [Google Scholar]
  • 46.Rauktys A, Lee N, Lee L, Dabora SL. Topical rapamycin inhibits tuberous sclerosis tumor growth in a nude mouse model. BMC Dermatol. 2008;8:1–1. doi: 10.1186/1471-5945-8-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Krueger DA, Care MM, Agricola K, et al. Safety and efficacy of RAD001 (everolimus) for the treatment of subependymal giant cell astrocytoma in pediatric and adult patients with TSC. Presented at the TSC International Research Conference, University of Sussex; September 11–13, 2008; Brighton, UK.
  • 48.Zeng L-H, Xu L, Gutmann DH, Wong M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol. 2008;63:444–453. doi: 10.1002/ana.21331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Meikle L, Pillizzi K, Egnor A, et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signalling lead to improved survival and function. J Neurosci. 2008;28:5422–5432. doi: 10.1523/JNEUROSCI.0955-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Krueger DA, Holland-Bouley K, Byers AW, et al. Effect of RAD001 (everolimus) on epilepsy and neurocognition in patients with TSC. Presented at the TSC International Research Conference, University of Sussex; September 11–13, 2008; Brighton, UK.
  • 51.Chen X, Garelick MG, Wang HB, Athos J, Storm DR. PI3 kinase signalling is required for retrieval and extinction of contextual memory. Nat Neurosci. 2005;8:925–931. doi: 10.1038/nn1482. [DOI] [PubMed] [Google Scholar]
  • 52.Dash PK, Orsi SA, Moore AN. Spatial memory formation and memory-enhancing effect of glucose involves activation of the tuberous sclerosis complex-mammalian target of rapamycin pathway. J Neurosci. 2006;26:8048–8056. doi: 10.1523/JNEUROSCI.0671-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.de Vries PJ. The Neuroscience of TSC — are we at risk of getting lost between the bench and the bedside? Presented at the International TSC Research Conference: From DNA to Human Therapies; September 23–26, 2009; Chicago.

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