Neurofibromatosis type 1 (NF1)

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by a heterozygous loss-of-function mutation in the NF1 gene. NF1 has a birth incidence of approximately 1:2000. The partial inactivation of the NF1 gene can cause variable symptoms affecting skin, bone and nervous system and NF1 is also associated with an increased risk of benign and malignant tumor formation. NF1 is frequently associated with cognitive disabilities. These cognitive deficits include deficits in attention, visual-spatial abilities, motor learning, executive functioning, and intelligence (Krab, The Journal of Pediatrics, 2009, 2008).

NF1 cognitive research.
The ENCORE NF1 expertise center at Erasmus MC has a long history of research into the cognitive problems associated with NF1. Recently, in a study with 500 children we showed that although the mean full-scale intelligence quotient of children with NF1 is shifted to the left (mean IQ 88), the variability in cognitive ability is similar to the general population (Ottenhoff, Genet Med, 2020). This indicates that the presence of the NF1 mutation is affecting IQ with about 12 points, regardless the type of mutation in NF1. Only in NF1 individuals with a chromosomal deletion, this shift is significantly larger. This also indicates that there is no significant role of so called ‘modifier genes’ that can potentially change the effect of NF1 on brain function.

Studies of the cellular mechanism underlying the cognitive deficits associated with NF1 have largely focused on animal models of NF1. Based on these studies, the hypothesized cause of cognitive disabilities results from increased activity of inhibitory interneurons that decreases synaptic plasticity. Whether changes in neuronal plasticity are also underlying the cognitive deficits in NF1 patients is unknown. To investigate the role of cortical plasticity in the cognitive deficits in adults with NF1, we use non-invasive neurophysiological measures as transcranial magnetic stimulation (TMS) and electroencephalography (EEG).

Despite several clinical trials aimed at improving cognitive deficits in NF1, we have not been able to identify an effective treatment yet (Krab, The Journal of the American Medical Association, 2008). Statins improved neuronal plasticity and learning deficits in a Nf1 mouse model, however, it had no effect on cognitive function, attention and behavior in NF1 children (Van de Vaart, The Lancet Neurology, 2013). Furthermore, the ENCORE-laboratory has shown that the cognitive deficits in Nf1 mice are caused by impaired function of HCN1-channels (hyperpolarization-activated cyclic nucleotide-gated channels) (Omrani, Molecular Psychiatry, 2015). An agonist (stimulator) of the HCN1 channel, lamotrigine, could rescue deficits in inhibition and plasticity in animal models of NF1. Whether this is also the case in human, is currently being investigated by means of a randomized controlled trial.

Ongoing clinical studies.
VEP-NF1 study: to investigate plasticity in the visual cortex in NF1 patients, we measure visual evoked potentials (VEPs) in response to visual stimulation. Additionally, to study the ability and efficiency of the visual system to perform actions, we assess eye- and hand-tracking measures during specific coordination tasks

NF1 Tumor-related research.

NF1 patients are predisposed to develop cancer. Almost all individuals with NF1 present with benign, dermal neurofibromas associated with peripheral nerves. Many also develop deeper-seated plexiform neurofibromas that may transform, through a distinct intermediary, precursor lesion atypical neurofibromas, into malignant peripheral nerve sheath tumors (MPNST). NF1 patients have life-time risk of 8 – 16% to develop MPNST which are a major cause of mortality in this patient group. MPNST are aggressive soft tissue sarcomas that metastasize easily and are therapy resistant translating into a dismal prognosis particularly for those patients confronted with unresectable or advanced disease. In the department of Medical oncology, Erasmus MC, the determining factors and molecular drivers underlying the malignant transformation of PNF into MPNST are being studied with a particular interest for microRNAs. We demonstrated that deregulated microRNAs in MPNST contribute to cancer-related processes such the ability to invade surrounding tissue and to metastasize (Amirnasr, Scientific Reports, 2020). A better understanding of the precise involvement of microRNAs in MPNST – and atypical neurofibromas and plexiform neurofibromas – biology may yield novel, more effective, therapeutic strategies. Another research goal is to identify biomarkers e.g. microRNAs in the NF1 patient’s circulation that signal the development of MPNST enabling clinical intervention at an early stage.

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