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.

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