In order to provide the best possible care to patients with a rare condition, it is essential that global knowledge about the condition is gathered. Nationwide, centers of expertise have been set up to stimulate care for rare disorders and to gather knowledge. For the formal recognition of an expertise center by the Ministry of Health, an important condition is that the expertise center gathers, analyzes and shares knowledge through publications. These can be publications in scientific journals, but also treatment guidelines for health care professionals or information brochures for patients or caregivers. We optimize care and research within ENCORE through standardized follow-up and close collaboration between doctors and researchers. That way, we can ultimately develop better treatments for rare conditions. You may therefore be asked to participate in research. Participation in research is always on a voluntary basis. The data obtained is stored and analyzed in an anonymous form. All research has been approved in advance by an ethics review committee.
Genetic testing will be performed on all TSC patients seen in our center of expertise to determine the genetic cause and to be able to support and advise the parents. If genetic testing has already been done elsewhere, it will not be repeated. This genetic knowledge also helps us to better understand the effect of the genetic change ("mutation") on the severity of symptoms. We can then also investigate which treatment works best for a particular mutation. In rare cases, the genetic analysis is inconclusive. In these cases, the genetic change will be further investigated in the laboratory.
Detailed knowledge about the course of TSC (which symptoms and complaints are there, and when exactly do they arise) is of great importance in order to be able to recognize complaints early in the future and to treat them optimally. In addition, this is of great importance for drug research (trials). After all, only if we can demonstrate that a new drug improves the quality of life compared to an untreated patient, will the drug actually be approved and reimbursed. If parents / child / patient give permission, their data will be included in our database. We work together with the UMCU TSC expertise center in the Netherlands, which is in the UMCU.
In addition to permission to record these clinical data, you may be asked to provide a tube of blood for research. This blood is used to generate iPSC (induced Pluripotent Stem Cells) for research. Brain cells can be grown from these iPS cells. See the pre-clinical research page on this website for more information about iPS research.
Clinical trials for new treatments for TSC
Studies at ENCOCRE's lab showed that TSC mice treated with an mTOR inhibitor (Sirolimus or Everolimus) no longer have epilepsy (see our pre-clinical research pages). We also saw positive results after treatment with Cannabidiol (CBD).
Within ENCORE we have conducted two clinical trials to investigate if this also works in TSC patients:
RAPIT study: a study (double-blind and placebo-controlled) into the effect of mTOR inhibitory medication (Everolimus) on symptoms of autism and intellectual disability in children aged 4-17 years. 32 children participated and took medication for 12 months. Everolimus showed no positive effect on IQ or autism symptoms
RATE study: a study (double-blind, placebo-controlled) on the effect of mTOR inhibiting medication (Sirolimus) on seizure frequency in children with TSC and difficult-to-treat epilepsy. We saw a positive effect here. This has been confirmed in other studies and mTOR inhibition is now also used in clinical practice.
We have also participated in two large international studies for the treatment of difficult to treat epilepsy in TSC: with Everolimus (Novartis) and CBD (GW Pharma).
Müller AR, et.al. (2024) Cannabidiol (Epidyolex®) for severe behavioral manifestations in patients with tuberous sclerosis complex, mucopolysaccharidosis type III and fragile X syndrome: protocol for a series of randomized, placebo-controlled N-of-1 trials. BMC Psychiatry. Pubmed
Müller AR, et.al. (2023) Understanding the impact of tuberous sclerosis complex: development and validation of the TSC-PROM. BMC Med. Aug 8;21(1):298. Pubmed
Lubbers K, et.al. (2022) Autism Symptoms in Children and Young Adults With Fragile X Syndrome, Angelman Syndrome, Tuberous Sclerosis Complex, and Neurofibromatosis Type 1: A Cross-Syndrome Comparison. Front Psychiatry. Pubmed
Koene LM, et.al. (2021) Identifying the temporal electrophysiological and molecular changes that contribute to TSC-associated epileptogenesis. JCI Insight. 6(23):e150120. Pubmed
Koene LMC, et al. (2019) Effects of antiepileptic drugs in a new TSC/mTOR-dependent epilepsy mouse model. Ann Clin Transl Neurol. 6; 1273–91. Pubmed
Overwater IE, et al. (2019) A randomized controlled trial with everolimus for IQ and autism in tuberous sclerosis complex. Neurology. 93; E200–9. Pubmed
Overwater IE, et.al. (2019) Everolimus for the treatment of refractory seizures associated with tuberous sclerosis complex (TSC): Current perspectives. Ther Clin Risk Manag. 951–5. Pubmed
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Overwater IE, et al. (2017) Interdependence of clinical factors predicting cognition in children with tuberous sclerosis complex. J Neurol. 264; 161–7. Pubmed
Reijnders MRF, et al. (2017) Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability. Nat Commun. Pubmed
Overwater IE, et al. (2016) Genotype and brain pathology phenotype in children with tuberous sclerosis complex. Eur J Hum Genet. 24; 1688–95. Pubmed
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Goorden SMI, et.al. (2015) Intact neuronal function in Rheb1 mutant mice: implications for TORC1-based treatments. Hum Mol Genet 24; 3390–8. Pubmed
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Overwater IE, et.al. (2014) Treatment of intractable epilepsy in tuberous sclerosis complex with everolimus is not yet evidence-based. Ann Neurol. Pubmed
Abs, E. et al. (2013) TORC1-dependent epilepsy caused by acute biallelic Tsc1 deletion in adult mice. Ann Neurol 74, 569–579. Pubmed
Overwater, I.E. et al. (2013) Behandelingen voor genetische neurocognitieve aandoeningen. Neuropraxis 5, 132–138. Link
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Melser, S. et al. (2013) Rheb regulates mitophagy induced by mitochondrial energetic status. Cell Metabolism 17, 719–730. Pubmed
van Eeghen, A.M. et al. (2013) Central TSC2 missense mutations are associated with a reduced risk of infantile spasms. Epilepsy Res 103, 83–87. Pubmed
van Eeghen, A.M. et al. (2012) Understanding relationships between autism, intelligence, and epilepsy: a cross-disorder approach. Dev Med Child Neurol 55, 146–153. Pubmed
Hoogeveen-Westerveld, M. et al. (2012) Functional Assessment of TSC2 Variants Identified in Individuals with Tuberous Sclerosis Complex. Hum Mutat. Pubmed
van Eeghen, A.M. et al. (2012) Genotype and cognitive phenotype of patients with tuberous sclerosis complex. Eur J Hum Genet 20, 510–515. Pubmed
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Goorden, S.M.I. and Elgersma, Y. (2011) Rheb: enrichment beyond the brain. Cell Cycle 10, 2412–2413. Pubmed
van den Ouweland, A.M.W. et al. (2011) Characterisation of TSC1 promoter deletions in tuberous sclerosis complex patients. Eur J Hum Genet 19, 157–163. Pubmed
van Eeghen, A.M. et al. (2011) Characterizing sleep disorders of adults with tuberous sclerosis complex: a questionnaire-based study and review. Epilepsy Behav 20, 68–74. Pubmed
Goorden, S.M.I. et al. (2007) Cognitive deficits in Tsc1+/- mice in the absence of cerebral lesions and seizures. Ann Neurol 62, 648–655. Pubmed
Sancak, O. 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. Pubmed
Nellist, M. et al. (2005) Large deletion at the TSC1 locus in a family with tuberous sclerosis complex. Genet. Test. 9, 226–230. Pubmed
Nellist, M. et al. (2003) Regulation of tuberous sclerosis complex (TSC) function by 14-3-3 proteins. Biochem Soc Trans 31, 587–591. Pubmed
Nellist, M. et al. (2001) TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin-hamartin complex. Hum Mol Genet 10, 2889–2898. Pubmed
Goedbloed, M.A. et al. (2001) Analysis of TSC2 stop codon variants found in tuberous sclerosis patients. Eur J Hum Genet 9, 823–828. Pubmed
Nellist, M. et al. (1999) Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin. J Biol Chem 274, 35647–35652. Pubmed
Verhoef, S. et al. (1999) High rate of mosaicism in tuberous sclerosis complex. Am J Hum Genet 64, 1632–1637. Pubmed
van Slegtenhorst, M. et al. (1999) Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation. J Med Genet 36, 285–289. Pubmed
Verhoef, S. et al. (1999) Malignant pancreatic tumour within the spectrum of tuberous sclerosis complex in childhood. Eur J Pediatr 158, 284–287. Pubmed
van Slegtenhorst, M. et al. (1998) Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 7, 1053–1057. Pubmed
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Do you have questions about research at ENCORE? Or do you want to participate? Please contact us via encore@erasmusmc.nl or tubereuzesclerose@erasmusmc.nl