As critical regulators of brain homeostasis, microglia are influenced by numerous factors, including sex and genetic mutations. To study the impact of these factors on microglia biology, we employed genetically engineered mice that model Neurofibromatosis type 1 (NF1), a disorder characterized by clinically relevant sexually dimorphic differences. While microglia phagocytic activity was reduced in both male and female heterozygous Nf1 mutant (Nf1+/-) mice, purinergic control of phagocytosis was only affected in male Nf1+/- mice. ATP-induced P2Y-mediated membrane currents and P2RY12-dependent laser lesion-induced accumulation of microglial processes were also only impaired in male, but not female Nf1+/-, microglia. These defects resulted from Nf1+/- male-specific defects in cyclic AMP regulation, rather than from changes in purinergic receptor expression. Cyclic AMP elevation by phosphodiesterase blockade restored the male Nf1+/- microglia defects in P2Y-dependent membrane currents and process motility. Taken together, these data establish a sex-by-genotype interaction important to microglia function in the adult mouse brain.

Neurofibromatosis type 1 (NF-1) is an autosomal dominant disease that affects one in every 3000 individuals. This disease can present a wide range of clinical manifestations, ranging from skin abnormalities to severe vascular damage. Although not commonly recognized in the context of NF-1, cerebrovascular disease (CVD), can be often present since childhood and diagnosed just later in life. When present, NF-1-associated CVD clinical manifestations may include headache, cognitive deficits and ultimately aneurysm rupture, causing death. Thus, CVD plays an important role in the clinical manifestations, disease severity and prognosis of patients with NF-1. This systematic review aims to summarize the body of evidence linking NF-1 and CVD in children.

Neurofibromatosis type 1 (NF1) is a neurogenetic disorder affecting 1 in 3000 people worldwide, where individuals are prone to develop benign and malignant tumors. In addition, many people with NF1 complain of pain that limits their daily functioning. Due to the complexity of the disorder, there are few options for treating pain symptoms besides surgery and medications. Moreover, the spectrum of pain symptomatology and treatment, as well as the mechanisms underlying NF1-associated pain, has been understudied.

Neurofibromatosis, including type 1 and type 2, is inherited dominant disease that causes serious consequences. The genetic mechanism of these diseases has been described, but germline mutation of checkpoint 2 kinase gene, together with other DNA repair related genes, has not been fully elucidated in the context of neurofibromatosis.

To examine the impact of executive function disorders on health-related quality of life (QoL) in children with neurofibromatosis type 1 (NF1), we conducted a prospective single-center study among 40 children with NF1 aged 8-12 years (mean = 9.7, SD = 1.4) and their parents, comparing them with 56 healthy control children matched for age, sex, parental education level, and handedness. We collected children's self-reports and parents' proxy reports of QoL with the Kidscreen-52 questionnaire, and measured executive functions by combining seven performance-based tests and a daily life questionnaire completed by parents and teachers.

Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder characterized by a broad spectrum of cognitive deficits. In particular, executive dysfunction is recognized as a core deficit of NF1, including impairments in executive attention and inhibitory control. Yet, the neural mechanisms behind these important deficits are still unknown. Here, we studied inhibitory control in a visual go/no-go task in children and adolescents with NF1 and age- and gender-matched controls (n = 16 per group). We applied a multimodal approach using high-density electroencephalography (EEG), to study the evoked brain responses, and magnetic resonance spectroscopy (MRS) to measure the levels of GABA and glutamate + glutamine in the medial frontal cortex, a brain region that plays a pivotal role in inhibitory control, and also in a control region, the occipital cortex. Finally, we run correlation analyses to identify the relationship between inhibitory control, levels of neurotransmitters, and EEG markers of neural function. Individuals with NF1 showed impaired impulse control and reduced EEG correlates of early visual processing (parieto-occipital P1) and inhibitory control (frontal P3). MRS data revealed a reduction in medial frontal GABA+/tCr (total Creatine) levels in the NF1 group, in parallel with the already reported reduced occipital GABA levels. In contrast, glutamate + glutamine/tCr levels were normal, suggesting the existence of abnormal inhibition/excitation balance in this disorder. Notably, medial frontal but not occipital GABA levels correlated with general intellectual abilities (IQ) in NF1, and inhibitory control in both groups. Surprisingly, the relationship between inhibitory control and medial frontal GABA was reversed in NF1: higher GABA was associated with a faster response style whereas in controls it was related to a cautious strategy. Abnormal GABAergic physiology appears, thus, as an important factor underlying impaired cognition in NF1, in a level and region dependent manner.

In the neurofibromatosis type 1 (NF1) mouse model, lovastatin, used clinically for hypercholesterolemia, improves cognitive dysfunction. While such impairment has been studied in NF1, the neural substrates remain unclear. The aim of this imaging add-on to a Phase 1 open-label trial was to examine the effect of lovastatin on Default Network (DN) resting state functional connectivity (RSFC). Seven children with NF1 (aged 11.9 ± 2.2; 1 female) were treated with lovastatin once daily for 12 weeks. A 7-min 3-T echo-planar-imaging scan was collected one day before beginning treatment (off-drug) and the last day of treatment (on-drug) while performing a flanker task. After regressing-out task-associated variance, we used the residual time series as "continuous resting-state data" for RSFC analyses using 11 DN regions of interest. For qualitative comparisons, we included a group of 19 typically developing children (TDC) collected elsewhere. In the on-drug condition, lovastatin increased long-range positive RSFC within DN core regions (i.e., anterior medial prefrontal cortex and posterior cingulate cortex, PCC). In addition, lovastatin produced less diffuse local RSFC in the dorsomedial prefrontal cortex and PCC. The pattern of RSFC observed in the NF1 participants when on-drug closely resembled the RSFC patterns exhibited by the TDC. Lovastatin administration in this open trial regulated anterior-posterior long-range and local RSFC within the DN. These preliminary results are consistent with a role for lovastatin in normalization of developmental processes and with apparent benefits in a mouse NF1 model.

Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in NF1 and characterized by a heterogeneous phenotypic presentation. Relevant genotype-phenotype correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1. Of these, 365 subjects fulfilled ≥2 NIH criteria, including 235 pediatric patients. Genetic testing was performed through cDNA-based sequencing, Next Generation Sequencing (NGS), and Multiplex Ligation-dependent Probe Amplification (MLPA). Uni- and multivariate statistical analysis was used to investigate genotype-phenotype correlations. Among patients fulfilling ≥ 2 NIH criteria, causative single nucleotide variants (SNVs) and copy number variations (CNVs) were detected in 267/365 (73.2%) and 20/365 (5.5%) cases. Missense variants negatively correlated with neurofibromas (p = 0.005). Skeletal abnormalities were associated with whole gene deletions (p = 0.05) and frameshift variants (p = 0.006). The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations (p = 0.031), whereas Lisch nodules (p = 0.05) and endocrinological disorders (p = 0.043) were associated with the c.6855C>A; p.(Y2285*) variant. We identified novel NF1 genotype-phenotype correlations and provided an overview of known associations, supporting their potential relevance in the implementation of patient management.

Most craniofacial manifestations of neurofibromatosis type 1 (NF1) are considered as a result of tumor compression. We sought to determine salivary changes, caries, and periodontal complications in NF1 patients without tumors in the oral cavity.

Neurofibromatosis Type 1 (NF1) is a genetic disorder that disrupts central nervous system development and neuronal function. Cognitively, NF1 is characterized by difficulties with executive control and visuospatial abilities. Little is known about the neural substrates underlying these deficits. The current study utilized Blood-Oxygen-Level-Dependent (BOLD) functional MRI (fMRI) to explore the neural correlates of spatial working memory (WM) deficits in patients with NF1.

Neurofibromatosis 1 (NF1) is one of the most common dominantly inherited genetic disorders worldwide, with an age-dependent phenotypic expression. Exploring the mutational spectrum and clinical presentation of NF1 patients at different ages from a diverse population will aid the understanding of genotype-phenotype correlations.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that results from germline mutations of the NF1 gene, creating a predisposition to low-grade gliomas (LGGs; pilocytic astrocytoma) in young children. Insufficient data and resources represent major challenges to identifying the best possible drug therapies for children with this tumor. Herein, we summarize the currently available cell lines, genetically engineered mouse models, and therapeutic targets for these LGGs. Conspicuously absent are human tumor-derived cell lines or patient-derived xenograft models for NF1-LGG. New collaborative initiatives between patients and their families, research groups, and pharmaceutical companies are needed to create transformative resources and broaden the knowledge base relevant to identifying cooperating genetic drivers and possible drug therapeutics for this common pediatric brain tumor.

Neurofibromatosis type 1 (NF1) is a rare inherited neurocutaneous disorder with a major impact on the skin, nervous system and eyes. The ocular diagnostic hallmarks of this disease include iris Lisch nodules, ocular and eyelid neurofibromas, eyelid café-au-lait spots and optic pathway gliomas (OPGs). In the last years, new manifestations have been identified in the ocular district in NF1 including choroidal abnormalities (CAs), hyperpigmented spots (HSs) and retinal vascular abnormalities (RVAs). Recent advances in multi-modality imaging in ophthalmology have allowed for the improved characterization of these clinical signs. Accordingly, CAs, easily detectable as bright patchy nodules on near-infrared imaging, have recently been added to the revised diagnostic criteria for NF1 due to their high specificity and sensitivity. Furthermore, subclinical alterations of the visual pathways, regardless of the presence of OPGs, have been recently described in NF1, with a primary role of neurofibromin in the myelination process. In this paper, we reviewed the latest progress in the understanding of choroidal and retinal abnormalities in NF1 patients. The clinical significance of the recently revised diagnostic criteria for NF1 is discussed along with new updates in molecular diagnosis. New insights into NF1-related neuro-ophthalmic manifestations are also provided based on electrophysiological and optical coherence tomography (OCT) studies.

Neurofibromatosis 1 (NF1) is a rare autosomal dominant disease characterized by increased Schwann cell proliferation in peripheral nerves. Several small studies of brain morphology in children with NF1 have found increased total brain volume, total white matter volume and/or corpus callosum area. Some studies (mostly in children with NF1) also attempted to correlate changes in brain morphology and volume with cognitive or behavioural abnormalities, although the findings were inconsistent. We aimed to characterize alterations in brain volumes by three-dimensional (3D) MRI in adults with NF1 in major intracranial sub-regions. We also aimed to assess the effect of age on these volumes and correlated brain white matter and grey matter volumes with neuropsychometric findings in adults with NF1.

Malignant peripheral nerve sheath tumors (MPNST) are aggressive cancers that occur spontaneously (sporadic MPNST) or from benign plexiform neurofibromas in neurofibromatosis type 1 (NF1) patients. MPNSTs metastasize easily, are therapy resistant and are frequently fatal. The molecular changes underlying the malignant transformation in the NF1 setting are incompletely understood. Here we investigate the involvement of microRNAs in this process. MicroRNA expression profiles were determined from a series of archival, paired samples of plexiform neurofibroma and MPNST. Ninety differentially expressed microRNAs were identified between the paired samples. Three downregulated microRNAs (let-7b-5p, miR-143-3p, miR-145-5p) and two upregulated microRNAs (miR135b-5p and miR-889-3p) in MPNST were selected for functional characterization. In general, their differential expression was validated in a relevant cell line panel but only partly in a series of unpaired, fresh frozen tumor samples. As part of the validation process we also analyzed microRNA expression profiles of sporadic MPNSTs observing that microRNA expression discriminates NF1-associated and sporadic MPNSTs. The role of microRNAs in cancer progression was examined in NF1-derived MPNST cell lines by transiently modulating microRNA levels. Our findings indicate that some microRNAs affect migratory and invasive capabilities and Wnt signaling activity but the effects are distinct in different cell lines. We conclude that miRNAs play essential regulatory roles in MPNST facilitating tumor progression.

Neurofibromatosis type 1 (NF1) is a tumor predisposition genetic disorder that directly affects more than 1 in 3,000 individuals worldwide. It results from mutations of the NF1 gene and shows almost complete penetrance. NF1 patients show high phenotypic variabilities, including cafe-au-lait macules, freckling, or other neoplastic or non-neoplastic features. Understanding the underlying mechanisms of the diversities of clinical symptoms might contribute to the development of personalized healthcare for NF1 patients. Currently, studies have shown that the different types of mutations in the NF1 gene might correlate with this phenomenon. In addition, genetic modifiers are responsible for the different clinical features. In this review, we summarize different genetic mutations of the NF1 gene and related genetic modifiers. More importantly, we focus on the genotype-phenotype correlation. This review suggests a novel aspect to explain the underlying mechanisms of phenotypic heterogeneity of NF1 and provides suggestions for possible novel therapeutic targets to prevent or delay the onset and development of different manifestations of NF1.

Neurofibromatosis type (NF1) is a syndrome characterized by varied symptoms, ranging from mild to more aggressive phenotypes. The variation is not explained only by genetic and epigenetic changes in the NF1 gene and the concept of phenotype-modifier genes in extensively discussed in an attempt to explain this variability. Many datasets and tools are already available to explore the relationship between genetic variation and disease, including systems biology and expression data. To suggest potential NF1 modifier genes, we selected proteins related to NF1 phenotype and NF1 gene ontologies. Protein-protein interaction (PPI) networks were assembled, and network statistics were obtained by using forward and reverse genetics strategies. We also evaluated the heterogeneous networks comprising the phenotype ontologies selected, gene expression data, and the PPI network. Finally, the hypothesized phenotype-modifier genes were verified by a random-walk mathematical model. The network statistics analyses combined with the forward and reverse genetics strategies, and the assembly of heterogeneous networks, resulted in ten potential phenotype-modifier genes: AKT1, BRAF, EGFR, LIMK1, PAK1, PTEN, RAF1, SDC2, SMARCA4, and VCP. Mathematical models using the random-walk approach suggested SDC2 and VCP as the main candidate genes for phenotype-modifiers.

Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in Neurofibromin 1 (NF1). NF1 patients present with a variety of clinical manifestations and are predisposed to cancer development. Many NF1 animal models have been developed, yet none display the spectrum of disease seen in patients and the translational impact of these models has been limited. We describe a minipig model that exhibits clinical hallmarks of NF1, including café au lait macules, neurofibromas, and optic pathway glioma. Spontaneous loss of heterozygosity is observed in this model, a phenomenon also described in NF1 patients. Oral administration of a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor suppresses Ras signaling. To our knowledge, this model provides an unprecedented opportunity to study the complex biology and natural history of NF1 and could prove indispensable for development of imaging methods, biomarkers, and evaluation of safety and efficacy of NF1-targeted therapies.

Neurofibromatosis type 1 (NF1) is an autosomal disorder associated with numerous physical stigmata. Children with NF1 are at known risk for attention-deficit/hyperactivity disorder (ADHD), academic struggles, and significant social difficulties and adverse social outcomes, including bullying victimization. The primary aim of this study was to identify risk factors associated with bullying victimization in children with NF1 to better inform clinicians regarding targets for prevention and clinical intervention. Children and a parent completed questionnaires assessing the bully victim status, and parents completed a measure of ADHD symptoms. Analyses were completed separately for parent-reported victimization of the child and the child's self-report of victimization. According to the parent report, results suggest ADHD symptoms are a significant risk factor for these children being a target of bullying. Findings for academic disability were not conclusive, nor were findings related to having a parent with NF1. Findings indicate the need for further research into possible risk factors for social victimization in children with NF1. Results provide preliminary evidence that may guide clinicians working with children with NF1 and their parents in identifying higher-risk profiles that may warrant earlier and more intensive intervention to mitigate later risk for bullying victimization.

Neurofibromatosis type 1 (NF1) is a rare disease, affecting around 1 in 3500 individuals in the general population. The rarity of the disease contributes to the scarcity of the available diagnostic and therapeutic approaches. Multispectral imaging is a non-invasive imaging method that shows promise in the diagnosis of various skin diseases. The device utilized for the present study consisted of four sets of narrow-band LEDs, including 526 nm, 663 nm, and 964 nm for diffuse reflectance imaging and 405 nm LEDs, filtered through a 515 nm long-pass filter, for autofluorescence imaging. RGB images were captured using a CMOS camera inside of the device. This paper presents the results of this multispectral skin imaging approach to distinguish the lesions in patients with NF1 from other more common benign skin lesions. The results show that the method provides a potential novel approach to distinguish NF1 lesions from other benign skin lesions.