Neurofibromatosis type 1 (NF1)

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 NF1 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. ENCORE contributed to the improvement of NF1 diagnostics (van Minkelen, Clinical Genetics, 2013).

Within ENCORE we also looked at the effect of the type NF1 mutation on cognitive functions (IQ). We found that all different NF1 mutations produce similar effects, with the exception of the so-called chromosomal micro-deletion. NF1 patients with this mutation are more affected (Ottenhoff, Genetics in Medicine, 2020).

Detailed knowledge about the course of Neurofibromatosis type 1 (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 and treat them optimally in the future. 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. ENCORE has done a lot of research in this area, particularly with regard to cognitive functions, and the impact that this has on daily functioning. ENCORE has also conducted extensive research into the mechanisms underlying the cognitive problems in both patients and mouse models of NF1 (see "Our publications" and the preclinical research pages on this site).

Clinical trials
ENCORE has conducted a number of clinical trials to investigate if the cognitive problems in NF1 can be ameliorated. We found no indication that statins improved cognitive function. It is currently being investigated whether Lamotrigine can provide an improvement.

The TRAIN study
In addition to these cognitive trials, clinical trials are currently underway with a "MEK inhibitor" that focus on the treatment of the plexiform neurofibromas that occur in NF1. Plexiform neurofibromas can be very damaging cosmetically, but can also lead to neurological deficit, bone growth, blindness, severe pain and aggressive cancer. They are difficult to operate because they have too good blood flow. That is why medicines are badly needed. Recent research shows that children with NF1 and a non-operable plexiform neurofibroma benefited from medicinal treatment. As a result of this study, Erasmus MC will conduct a study with trametinib in adult NF1 patients with plexiform neurofibromas that cause complaints. Click here for English information on trialregister.nl about this study (including inclusion and exclusion criteria).

Neurophysiological outcome measures
For conducting cognitive trials, it is very important to be able to determine quickly and objectively in a small group of patients whether the drug may work or not. That is why we are now focusing on developing techniques to determine these "outcome measures". We do this for instance by using transcranial magnetic stimulation (TMS).

Bron: DOI: 10.3389/fneur.2018.01141

In addition, we use EEG measurements to measure the plasticity of the visual cortex by measuring "visual evoked potentials".

 

EU pearl
The ENCORE-NF1 expertise center participates in the consortium EU-pearl,, a collaboration between 8 hospitals, a number of pharmaceutical partners, and EFPIA, which aims to set up a framework for "multi-centre multinational platform trials" for a number of syndromes. ErasmusMC-NF1 is working group leader for "WP7 Neurofibromatosis". The overall goals are to establish a clinical research network for trials in NF in Europe, to develop platform trials for drug treatment of complications for NF, and to set up a long-term study of the history of NF manifestations. Click here for more information about the EU-pearl consortium.

Dhaenens BAE, et.al. (2021) Lessons learned from drug trials in neurofibromatosis: A systematic review. Eur J Med Genet. 2021 Jul 5:104281. Pubmed

Castricum J, Tulen JHM, Taal W, Rietman AB, Elgersma Y (2021). Attention and Motor Learning in Adult Patients with Neurofibromatosis Type 1. J Atten Disord. Pubmed

Dhaenens BAE, et.al. (2021). Identifying challenges in neurofibromatosis: a modified Delphi procedure. Eur J Hum Genet. 26:1–9 Pubmed

Fangusaro J, et.al. (2020) Response assessment in paediatric low-grade glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group. Lancet Oncol. 21(6); e305-16. Pubmed

Amirnasr A, et.al. (2020) Deregulated microRNAs in neurofibromatosis type 1 derived malignant peripheral nerve sheet tumors. Sci. Rep. 10:2927. Pubmed

Castricum J, et.al. (2020) Motor cortical excitability and plasticity in patients with neurofibromatosis type 1. Clin Neurophysiol. 131(11); 2673-81. Pubmed

Ottenhoff MJ, et al.(2020) Examination of the genetic factors underlying the cognitive variability associated with neurofibromatosis type 1. Genet Med.1-9. Pubmed

Frebourg T, et.al. (2020) Guidelines for the Li-Fraumeni and heritable TP53 related cancer syndromes. Eur J Hum Genet. 28(10); 1379-86. Pubmed

Siebelt M, et al. (2019) Congenital Forearm Pseudarthrosis, a Systematic Review for a Treatment Algorithm on a Rare Condition. J Pediatr Orthop. 40; e367-74. Pubmed

Vos JR, et.al. (2019) Boosting care and knowledge about hereditary cancer: European Reference Network on Genetic Tumour Risk Syndromes. Fam Cancer. 18(2); 281-4. Pubmed

Koczkowska M, et.al. (2019) Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation. Genet. Med. 21(4); 867-76. Pubmed

Rietman AB, et al. (2018) Emotional and behavioral problems in children and adolescents with neurofibromatosis type 1. Am J Med Genet B Neuropsychiatr Genet. 177; 319–28. Pubmed

Rietman AB, et al. (2018) Worries and needs of adults and parents of adults with neurofibromatosis type 1. Am J Med Genet A. 176; 1150–60. Pubmed

Eijk S, et al. (2018) Autism Spectrum Disorder in an Unselected Cohort of Children with Neurofibromatosis Type 1 (NF1). J Autism Dev Disord. 48; 2278–85. Pubmed

Amirnasr A, et.al. (2017) Expression and inhibition of BRD4, EZH2 and TOP2A in neurofibromas and malignant peripheral nerve sheath tumors. PLoS One. 12(8); e0183155. Pubmed

Rietman AB, et al. (2017) Development of emotional and behavioral problems in neurofibromatosis type 1 during young childhood. Am J Med Genet A. 173; 2373–80. Pubmed

Rietman AB, et al. (2017) Motor problems in children with neurofibromatosis type 1. J Neurodev Disord. Pubmed

van der Vaart T, et al. (2016) Behavioral and cognitive outcomes for clinical trials in children with neurofibromatosis type 1. Neurology 86;154–60. Pubmed

Omrani A, et al. (2015) HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1. Mol Psychiatry 20; 1311–21. Pubmed

Omrani A, et.al. (2015) Neurofibromin regulates HCN activity in Parvalbumin-positive interneurons. Mol Psychiatry. 20; 1263. Pubmed

Van Der Vaart, T. et al. (2013) Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial. Lancet Neurol 12, 1076–1083. Pubmed

van Minkelen, R. et al. (2013) A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands. Clin Genet. Pubmed

Acosta, M.T. et al. (2012) The Learning Disabilities Network (LeaDNet): using neurofibromatosis type 1 (NF1) as a paradigm for translational research. Am J Med Genet A 158, 2225–2232. Pubmed

van der Vaart, T. et al. (2011) Motor deficits in neurofibromatosis type 1 mice: the role of the cerebellum. Genes Brain Behav 10, 404–409. Pubmed

Krab, L.C. et al. (2011) Motor learning in children with neurofibromatosis type I. Cerebellum 10, 14–21. Pubmed

Krab, L.C. et al. (2009) Health-related quality of life in children with neurofibromatosis type 1: contribution of demographic factors, disease-related factors, and behavior. J Pediatr 154, 420–5, 425.e1. Pubmed

Denayer, E. et al. (2008) Spred1 is required for synaptic plasticity and hippocampus-dependent learning. J Neurosci 28, 14443–14449. Pubmed

Cui, Y. et al. (2008) Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell 135, 549–560. Pubmed

Krab, L.C. et al. (2008) Impact of neurofibromatosis type 1 on school performance. J Child Neurol 23, 1002–1010. Pubmed

Krab, L.C. et al. (2008) Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. JAMA 300, 287–294. Pubmed

Balgobind, B.V. et al. (2008) Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis. Blood 111, 4322–4328. Pubmed

van Engelen, S.J.P.M. et al. (2008) Quantitative differentiation between healthy and disordered brain matter in patients with neurofibromatosis type I using diffusion tensor imaging. AJNR Am J Neuroradiol 29, 816–822. Pubmed

Oostenbrink, R. et al. (2007) Parental reports of health-related quality of life in young children with neurofibromatosis type 1: influence of condition specific determinants. J Pediatr 151, 182–6– 186.e1–2. Pubmed

Cnossen, M.H. et al. (1998) Minor disease features in neurofibromatosis type 1 (NF1) and their possible value in diagnosis of NF1 in children. J Med Genet 35, 624–627. Pubmed

Cnossen, M.H. et al. (1998) A prospective 10 year follow up study of patients with neurofibromatosis type 1. Arch. Dis. Child. 78, 408–412. Pubmed

Cnossen, M.H. et al. (1997) Endocrinologic disorders and optic pathway gliomas in children with neurofibromatosis type 1. Pediatrics 100, 667–670. Pubmed

Cnossen, M.H. et al. (1997) Diagnostic delay in neurofibromatosis type 1. Eur J Pediatr 156, 482–487. Pubmed

Cnossen, M.H. et al. (1997) Deletions spanning the neurofibromatosis type 1 gene: implications for genotype-phenotype correlations in neurofibromatosis type 1? Hum Mutat 9, 458–464. Pubmed

Do you have questions about research at ENCORE? Or do you want to participate? Please contact us via info@encore-expertisecentrum.nl or nf1centrum@erasmusmc.nl