Distinct attentional and executive profiles in neurofibromatosis type 1: Is there difference with primary attention deficit-hyperactivity disorder?

PURPOSE: Attentional and executive dysfunctions are the most frequent cognitive disorders in neurofibromatosis type 1 (NF1), with a high prevalence of attention deficit-hyperactivity disorder (ADHD). We (i) compared attentional profiles between NF1 children with and without ADHD and children with primary ADHD criteria and (ii) investigated the possible relationship between attentional disorders and "unidentified bright objects" (UBOs) in NF1. METHODS: This retrospective study included 47 NF1 children, 25 with ADHD criteria (NF1+adhd group), matched for age, sex, and cognitive level with 47 children with primary ADHD (ADHD group). We collected computer task (sustained-attention, visuomotor-decision, inhibition, and cognitive-flexibility tasks) scores normalized for age and sex, and brain magnetic resonance imaging data. RESULTS: (i) Working memory was impaired in all groups. (ii) Omissions (p < 0.002) and response-time variability (p < 0.05) in sustained-attention and visuomotor-decision tasks and errors (p < 0.02) in the cognitive-flexibility task were lower for the NFI+adhd and ADHD groups than for the NF1-no-adhd group. (iii) The NF1+adhd group had slower response times (p ≤ 0.02) for inhibition and visuomotor-decision tasks than the other groups. (iv) We found no relevant association between cognitive performance and UBOs. CONCLUSIONS: NF1 children with ADHD have an attentional and executive functions deficit profile similar to that of children with primary ADHD, but with a slower response-time, increasing learning difficulties. The atypical connectivity of fronto-striatal pathways, poorer dopamine homeostasis, and increased GABA inhibition observed in NF1 renders vulnerable the development of the widely distributed neural networks that support attentional, working-memory, and executive functions.

The impact of cutaneous neurofibromas on quality of life and mental health in neurofibromatosis type 1.

The skin manifestations of neurofibromatosis 1 significantly reduce health-related quality-of-life. However, data on the utility of existing surveys in capturing neurofibromatosis 1 skin treatment outcomes are lacking. This quantitative study examined the relationship between clinician-rated severity and visibility and patient-rated itch and quality-of-life (QoL) to (1) establish baseline levels of skin- and condition-specific-related QoL, itch, depression and anxiety; (2) identify patient concerns to inform the development and evaluation of skin interventions; and (3) compare the sensitivity of different QoL measures. Validated scales included Skindex-29, Dermatology Life Quality Index (DLQI), Neurofibromatosis 1-adult quality-of-life (NF1-AdQOL) questionnaire, and the Hospital Anxiety and Depression Scale (HADS). We recruited 100 participants (response rate: 95%). Of these, 42% reported itch and 23% had probable clinical anxiety. Our cohort had higher levels of anxiety and total HADS scores compared to a control population. Using multivariate regression analysis, increasing visibility significantly predicted poorer QoL using the Skindex-29, NF1-AdQOL, and DLQI (p < 0.05); and itch significantly predicted worse QoL in Skindex-29 and NF1-AdQOL (p < 0.05). The highest mean scoring questions in Skindex-29 and NF1-AdQOL concerned worry about worsening skin disease and embarrassment. The highest mean scoring questions in DLQI were regarding itch, pain, and embarrassment. Items asking specifically about cutaneous neurofibromas (cNF) scored higher than comparable skin-specific questions (t-test p value <0.05). In summary, this study provides insights into the factors contributing to impaired QoL, anxiety, and mood in NF1 patients with cutaneous neurofibromas. Key factors identified for use in cNF measures include visibility, itch, anxiety, embarrassment, fears of worsening skin disease, and cNF-specific questions.

Quality of life in individuals with neurofibromatosis type 1 associated cutaneous neurofibromas: validation of the Dutch cNF-Skindex.

BACKGROUND: Almost all patients with Neurofibromatosis type 1 (NF1) develop cutaneous neurofibroma (cNF), benign dermal tumours that have a large impact on the patient's Quality of Life (QoL). The French cNF-Skindex is the first questionnaire to specifically assess cNF-related QoL in patients with NF1. We aimed to adapt and validate a Dutch version of the cNF-Skindex. METHODS: The questionnaire was translated using forward and backwards translation, and subsequently administered to a sample of 59 patients on two separate occasions. Feasibility was evaluated by the presence of floor/ceiling effects. Reliability was assessed by evaluating internal consistency and test-retest reliability, by calculating Cronbach's alpha and Spearman's rank correlation coefficients. The EQ-5D-5L and SF-36 were used to evaluate convergent validity, using Spearman's rank correlation coefficients. An exploratory factor analysis was performed to study the data's internal structure. Multivariable linear regression was used to model the relationship between patient characteristics and the cNF-Skindex. RESULTS: The Dutch cNF-Skindex demonstrated excellent feasibility and reliability (Cronbach's alpha 0.96, test-retest correlation coefficient 0.88). Convergent validity was confirmed for the EQ-5D-5L and relevant SF-36 scales. All items and subdomains from the original questionnaire were confirmed following exploratory factor analysis. The patient characteristics included in the multivariable linear regression were not significantly associated with the cNF-Skindex score. CONCLUSIONS: The Dutch cNF-Skindex displayed excellent psychometric properties, enabling use in the Netherlands.

Impact of trametinib on the neuropsychological profile of NF1 patients.

PURPOSE: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. METHODS: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. RESULTS: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. CONCLUSION: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.

Association of sociodemographic and clinical factors with the quality of life of Brazilian individuals with Neurofibromatosis type 1: a cross-sectional study.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a rare genetic disorder with a wide range of clinical manifestations, notably neurocutaneous features, that can lead to emotional and physical consequences. OBJECTIVES: This study assessed the influence of sociodemographic factors and clinical features of the disease on the quality of life of Brazilian individuals with NF1. METHODS: This is a descriptive cross-sectional study. Data were collected from 101 individuals with NF1 using the Brazilian version of the Impact of NF1 on Quality of Life Questionnaire (INF1-QoL), a form with information on sociodemographic characteristics, and an NF1 visibility self-evaluation scale. The relationship between variables was evaluated through statistical testing, and the significance level was defined as 0.05. RESULTS: The study included 101 adults with NF1 aged 18 to 59 years, with a mean age of 35.54 years (±9.63) and a female predominance (n = 84, 83.17%). The mean total INF1-QoL score was 10.62 (±5.63), with a median of 10, minimum value of 0, and maximum of 31 points. Two characteristics of the participants were significantly associated with the quality of life: educational level (p = 0.003) and familial history of NF1 (p = 0.019). There was a statistically significant correlation between the INF1-QoL score and the degree of disease visibility (rho = 0.218; p = 0.028). STUDY LIMITATIONS: Cross-sectional study, conducted with a convenience sample and using self-reported measures. CONCLUSIONS: The findings support the significant impact of NF1 on quality of life. The authors recommend multidisciplinary follow-up for patients, with adherence to anticipatory clinical care measures, adequate pain control, psychological assistance, and genetic counseling.

Perceived transition readiness among adolescents and young adults with neurofibromatosis type 1 and plexiform neurofibromas: a cross-sectional descriptive study.

OBJECTIVES: Neurofibromatosis type 1 (NF1) is a genetic cancer predisposition syndrome that can impact multiple organ systems and is associated with plexiform neurofibroma tumors, requiring care from birth through adulthood. Adolescents and young adults (AYAs) with NF1 face several barriers to transition from pediatric to adult care. This cross-sectional study aimed to assess transition readiness in this population and to evaluate relationships between specific NF1 symptoms and transition readiness. METHODS: AYAs (aged 16-24) enrolled in existing studies related to NF1 were eligible. AYAs and their parents completed measures of transition readiness (Transition Readiness Assessment Questionnaire version 4 [TRAQ-4]), and AYAs also completed a transition readiness interview (UNC TRxANSITION). RESULTS: Thirty-eight AYAs (mean age = 19.95 ± 2.68 years) participated in the study. Average TRAQ scores indicated that AYAs were still learning Self-Management skills (M = 3.37, SD = 1.08) and Self-Advocacy skills (M = 3.98, SD = 0.67). Older AYAs had higher TRAQ scores for Self-Management (r = 0.70, p < .001) and Self-Advocacy (r = 0.41, p = .011) than younger AYAs. Parents and AYAs had similar TRAQ scores. About one third of AYAs (37.8%, n = 14) expressed uncertainty about how NF1 might affect them in the future. The remaining AYAs mostly expressed concerns regarding tumor growth, pain, or cancer. CONCLUSIONS: In this small study, preliminary findings suggest that AYAs with NF1 express confidence in many areas of transition readiness but continue to require support, particularly with Self-Management skills. Given the gaps in understanding of future health risks, AYAs with NF1 would benefit from early assessment, psychoeducation, and support for transition readiness to adult care.

An evaluation of computerized attention and executive function measures for use with school age children with neurofibromatosis type 1.

The present study investigated the performance of children with neurofibromatosis type 1 on computerized assessments of attention and executive function. Relations to ADHD symptomatology were also examined. Participants included 37 children (20 male) with NF1 (9-13 years; Mage = 11.02). Participants completed the NIH Toolbox Dimensional Change Card Sort, List Sort Working Memory (LSWM), and Flanker tasks, as well as Cogstate Identification and One Back tests. ADHD symptomatology was assessed using the K-SADS. Average performance was significantly different from the normative mean on every measure, except LSWM. The NIH Toolbox Flanker and Cogstate Identification tasks detected the highest proportion of participants with at least mild difficulty, and the Cogstate Identification task detected the highest proportion of participants with severe difficulty. Analyses revealed significant relations with ADHD symptomatology for two NIH toolbox tasks. The various computerized measures of attention and executive function offer different information when working with school age children with NF1. The NIH Flanker may offer the most room for change and offers face validity, which may be beneficial for clinical trials research. However, the LSWM shows most support for relations with behavioral indicators of attention and executive challenges.

Perspectives of adults with neurofibromatosis regarding the design of psychosocial trials: Results from an anonymous online survey.

BACKGROUND/AIMS: Individuals with neurofibromatosis, including neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2)-related schwannomatosis (SWN), and other forms of SWN, often experience disease manifestations and mental health difficulties for which psychosocial interventions may help. An anonymous online survey of adults with neurofibromatosis assessed their physical, social, and emotional well-being and preferences about psychosocial interventions to inform clinical trial design. METHODS: Neurofibromatosis clinical researchers and patient representatives from the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration developed the survey. Eligibility criteria included age ≥ 18 years, self-reported diagnosis of NF1, NF2, or SWN, and ability to read and understand English. The online survey was distributed internationally by the Neurofibromatosis Registry and other neurofibromatosis foundations from June to August 2020. RESULTS: Surveys were completed by 630 adults (18-81 years of age; M = 45.5) with NF1 (78%), NF2 (14%), and SWN (8%) who were mostly White, not Hispanic/Latino, female, and from the United States. The majority (91%) reported that their neurofibromatosis symptoms had at least some impact on daily life. In the total sample, 51% endorsed a mental health diagnosis, and 27% without a diagnosis believed they had an undiagnosed mental health condition. Participants indicated that neurofibromatosis affected their emotional (44%), physical (38%), and social (35%) functioning to a high degree. Few reported ever having participated in a drug (6%) or psychosocial (7%) clinical trial, yet 68% reported they "probably" or "definitely" would want to participate in a psychosocial trial if it targeted a relevant concern. Top treatment targets were anxiety, healthier lifestyle, and daily stress. Top barriers to participating in psychosocial trials were distance to clinic, costs, and time commitment. Respondents preferred interventions delivered by clinicians via individual sessions or a combination of group and individual sessions, with limited in-person and mostly remote participation. There were no significant group differences by neurofibromatosis type in willingness to participate in psychosocial trials (p = 0.27). Regarding interest in intervention targets, adults with SWN were more likely to prefer psychosocial trials for pain support compared to those with NF1 (p < 0.001) and NF2 (p < 0.001). CONCLUSION: This study conducted the largest survey assessing physical symptoms, mental health needs, and preferences for psychosocial trials in adults with neurofibromatosis. Results indicate a high prevalence of disease manifestations, psychosocial difficulties, and untreated mental health problems in adults with neurofibromatosis and a high degree of willingness to participate in psychosocial clinical trials. Patient preferences should be considered when designing and implementing psychosocial interventions to develop the most feasible and meaningful studies.

Understanding nonliteral language abilities in children with neurofibromatosis type 1.

OBJECTIVE: Neurofibromatosis Type 1 (NF1) is a genetic syndrome that affects cognitive, behavioral, and social development. Nonliteral language (NLL) comprehension has not been examined in children with NF1. This study examined NLL comprehension in children with NF1 and associated neuropsychological correlates. METHOD: NLL comprehension was examined in children with NF1 (n = 49) and typically developing (TD) controls (n = 27) aged 4-12 years using a novel NLL task. The task assessed comprehension of sarcasm, metaphor, simile, and literal language. Cognitive (Wechsler Scales Composites or the Woodcock-Johnson Test of Cognitive Abilities Revised scaled scores) and behavioral (attention deficit hyperactivity disorder [ADHD] symptoms) correlates of NLL comprehension in children with NF1 were also examined. RESULTS: Children with NF1 demonstrated significantly poorer sarcasm comprehension than TD children and a vulnerability in metaphor comprehension. Simile and literal language comprehension were not significantly different between groups. Working memory difficulties and impulsive/hyperactive ADHD symptoms were associated with a reduced ability to identify sarcasm in NF1, while verbal comprehension, fluid reasoning, and inattentive ADHD symptoms were not. CONCLUSIONS: Results suggest children with NF1 experience challenges in understanding complex NLL comprehension, which are related to reduced working memory and increased impulsivity/hyperactivity. This study provides an initial insight into the figurative language abilities of children with NF1, which should be examined in relation to their social difficulties in future studies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Longitudinal association between executive function and academic achievement in children with neurofibromatosis type 1 and plexiform neurofibromas.

OBJECTIVE: To examine how executive functioning (EF) relates to academic achievement longitudinally in children with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) and whether age at baseline moderates this relationship. METHOD: Participants included 88 children with NF1 and PNs (ages 6-18 years old, M = 12.05, SD = 3.62, 50 males) enrolled in a natural history study. Neuropsychological assessments were administered three times over 6 years. EF (working memory, inhibitory control, cognitive flexibility, and attention) was assessed by performance-based (PB) and parent-reported (PR) measures. Multilevel growth modeling was used to examine how EF at baseline related to initial levels and changes in broad math, reading, and writing across time, controlling for demographic variables. RESULTS: The relationship between EF and academic achievement varied across EF and academic domains. Cognitive flexibility (PB) uniquely explained more variances in initial math, reading, and writing scores; working memory (PB) uniquely explained more variances in initial levels of reading and writing. The associations between EF and academic achievement tended to remain consistent across age groups with one exception: Lower initial levels of inhibitory control (PR) were related to a greater decline in reading scores. This pattern was more evident among younger (versus older) children. CONCLUSIONS: Findings emphasize the heterogeneous nature of academic development in NF1 and that EF skills could help explain the within-group variability in this population. Routine cognitive/academic monitoring via comprehensive assessments and early targeted treatments consisting of medication and/or systematic cognitive interventions are important to evaluate for improving academic performance in children with NF1 and PNs.

Presence of neurologic signs in children with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 is a common neurogenetic disorder affecting nervous system, caused by germiline mutations of the NF1 gene. Although the clinical diagnosis of NF1 is defined by presence of cafe-au-laits spots, freckling and benign tumors (neurofibromatosis), neurocognitive impairment and neuropsychiatric disorders are reported in comorbidity. Children with NF1 show higher incidence of executive deficits, such attention, response inhibition, executive planning and problem solving, working memory, and learning impairment. In this study we examine the presence of neurological soft signs and planning function in subjects with NF1. The NSS are minor motor and sensory abnormalities without focal brain damage. METHODS: Eleven drug naïve children between 7-15 years with clinical and molecular diagnosis of NF are matched to 11 healthy controls to ass the presence of neurological soft signs and planning executive functions. NSS were assessed using Physical and Neurological Examination for Subtle Signs and the Tower of London task is performance test to assess the capacity of planning, organization and execution of a work. RESULTS: Our results revealed highest rate of NSS and planning deficit in children with NF1 compared to healthy controls. CONCLUSIONS: The motor abnormalities and planning deficit are possible markers to confirm that NF1 could be considering a neurodevelopmental disorder.

Understanding the Neurofibromatosis Type 1 (NF1) experience and the priorities of individuals with NF1 and their caregivers for cognitive and social-emotional research.

BACKGROUND: Patient engagement is increasingly recognized as a valuable, essential aspect of Neurofibromatosis research given the unique experiences and morbidities associated with the diagnosis. Engaging patients and families can enhance the relevance, methodology, and feasibility of clinical trials. METHODS: A REDCap survey ascertaining information on NF-related morbidities, priorities, and interests in cognitive and social-emotional research, and willingness to participate in research was dispensed to 4,565 individuals consented to the Children's Tumor Foundation (CTF) Registry with NF1. This included children and adults with NF1 and parents/caregivers of children with NF1. RESULTS: 525 individuals fully completed the survey: 295 parents/caregivers (Mage child = 10.12, range = 3-24), 194 adults with NF1 (Mage = 45.73, range = 19-81), and 36 children with NF1 (Mage = 12.61, range = 10-17). Less than 10% of respondents have participated in cognitive research, while 42.4-49.5% indicated having sought opportunities for cognitive research. Most (79.4-82.4%) respondents reported that cognitive research is very/extremely important, with learning/academics and emotional functioning were priorities. Willingness to participate in research aligned with areas of importance. CONCLUSION: Analysis highlights that most survey respondents believe cognitive and social-emotional research is very important, but a relatively small number have participated. This finding may highlight poor dissemination of information of research opportunities to the broader NF community and limitations to access based on geography or other factors. Respondents indicate that learning/academic problems and emotional challenges to be research priorities. Continuing to engage patients and families with NF is expected to enhance the value and engagement in cognitive research.

Baseline characteristics of adults with neurofibromatosis enrolled on a psychosocial randomized controlled trial.

PURPOSE: Neurofibromatosis (NF) is an incurable genetic neurological condition. Psychosocial interventions that promote resiliency are a promising approach to address the high emotional distress and low quality of life (QoL) associated with NF. However, no studies have examined the psychosocial needs of treatment-seeking adults with NF. Our goal was to explore, using data from the largest efficacy trial of a psychosocial intervention for NF, differences in QoL, emotional distress, resiliency, and pain-related outcomes compared to other chronic medical populations and within subtypes (NF1, NF2, schwannomatosis; SCHW). METHODS: Enrolled participants (N = 228) were geographically diverse adults with NF and elevated stress. We performed secondary analysis on baseline measures of QoL, emotional distress, resiliency, and pain-related outcomes. We reported descriptive statistics and normative comparisons to understand the psychosocial characteristics of the overall sample and performed between-group analyses to explore differences within NF type. RESULTS: Our sample endorsed worse QoL, emotional distress, resilience, and pain-related outcomes than similar chronic illness populations. Within NF types, participants with NF1 reported lower QoL and resilience compared to those with NF2. Participants with SCHW reported higher pain intensity than those with NF1. Participants with SCHW reported higher pain interference and lower physical QoL compared to those with NF1 and NF2. CONCLUSIONS: Our findings support the urgent need for psychosocial interventions targeting deficits in QoL, emotional distress, resilience, and pain-related outcomes in adults with NF. We recommend efforts to enhance sample diversity, prepare clinicians to provide high-levels of support, and attune skills training to each NF type. TRIAL REGISTRATION: ClinicalTrials.gov NCT03406208; https://clinicaltrials.gov/ct2/show/NCT03406208 (Archived by WebCite at http://www.webcitation.org/72ZoTDQ6h ).

School performance of children with neurofibromatosis 1: a nationwide population-based study.

Children with neurofibromatosis 1 (NF1) may have a high burden of somatic disease and cognitive impairments, which can lead to poor academic performance. We evaluated school grades from exams ending mandatory schooling (usually around age 15 or 16 years) of children with NF1 in a population-based registry study using a within-school matched design. The study included 285 children with NF1 and 12,000 NF1-free peers who graduated from the same school and year during 2002-2015. We estimated overall and gender-specific grades by subject and compared the grades of children with NF1 with those of NF1-free peers in linear regression models. We also examined the effect of social and socioeconomic factors (immigration status and parental education, income and civil status) on grades and age at finalizing ninth grade. School grades varied considerably by socioeconomic stratum for all children; however, children with NF1 had lower grades by an average of 11-12% points in all subjects. In the adjusted models, children with NF1 had significantly lower grades than their NF1-free peers, with largest negative differences in grades observed for girls with NF1. Finally, children with NF1 were 0.2 (CI 0.1-0.2) years older than their peers on graduating from ninth grade, but only maternal educational modified the age at graduating. In conclusion, students with NF1 perform more poorly than their peers in all major school subjects. Gender had a strong effect on the association between NF1 and school grades; however, socioeconomic factors had a similar effect on grades for children with NF1 and their peers.

Quality of life in neurofibromatosis 1: development and validation of a tool dedicated to cutaneous neurofibromas in adults.

BACKGROUND: Cutaneous neurofibromas (cNF), present in 95% of individuals with neurofibromatosis 1 (NF1), are considered as one of the greatest medical burden because of physical disfigurement. No specific score evaluates their impact on quality of life (QoL). OBJECTIVE: To develop a specific score assessing cNF-related QoL. METHODS: Through a multidisciplinary workshop including 10 patients, 3 expert-in-NF1 physicians, 3 health care workers (nurses and psychologist) and 1 methodologist, the French version of the Skindex-16 was modified by adding 3 items. The new cNF-Skindex was validated among patients with NF1 recruited in the ComPaRe online cohort, in France (N = 284). Construct validity was assessed by comparing it with the EQ-5D-5L, its visual analogue scale and the MYMOP2 and by assessing its association with patients' characteristics. Reliability was assessed by a test-retest. An English version of the tool was developed using a back-forward translation. RESULTS: A total of 228 individuals with NF1, with cNF answered the 19-item questionnaire. These items fitted into 3 domains: emotions, symptoms, functioning. One was dropped during analysis because >90% responders were not concerned. The cNF-Skindex significantly correlated with the EQ-5D-5L (N = 193) and MYMOP2 (N = 210) indicating good external validity: rs 0.38 (P < 0.001), and 0.58 (P < 0.001), respectively. Having >50 cNF was the only independent variable associated with the total score cNF-Skindex (ß = 15.88, 95%CI 6.96-24.81, P = 0.001), and with the 3 sub-scores: 'functioning' (ß = 2.65, 95%CI 0.71-4.59, P = 0.008), 'emotions' (ß = 17.03, 95%CI 4.11-29.96, P = 0.010) and 'symptoms' (ß = 3.90, 95%CI 1.95-5.85, P < 0.001). Test-retest reliability (N = 133) found an ICC at 0.96 demonstrating good reproducibility. CONCLUSION: The cNF-Skindex demonstrated excellent psychometric properties. The global and sub-scores were increased with higher number of cNF arguing for its use in further trials aiming to reduce their number or prevent their development. Cross-cultural validation and evaluation of its responsiveness are the next steps.

Verbal learning and memory in youth with neurofibromatosis type 1 and plexiform neurofibromas: Relationships with disease severity.

AIM: To provide a comprehensive characterization of verbal learning and memory (VLM) abilities in youth with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) and to evaluate disease severity as a predictor of VLM functioning over time. METHOD: As part of a longitudinal natural history study, youth with NF1 and PNs were administered repeat neuropsychological assessments, including measures of VLM and ratings of NF1 disease severity completed by a medical professional. This sub-study analyzed data from 89 patients (M age baseline = 13.1, SD = 4.3 years, range 6-24 years) who had completed tests of VLM abilities and verbal attention at either baseline and/or 36 months. RESULTS: VLM scores across the sample fell predominantly within the average range of functioning at both time points. However, relative to peers with mild NF1 disease severity, youth with moderate/severe NF1 disease showed lower functioning across multiple VLM domains at 36 months, even after controlling for the effects of verbal attention. INTERPRETATION: Exclusive use of overall domain scores does not fully characterize VLM functioning in youth with NF1 and PNs. Additionally, children and adolescents with more severe NF1 disease should be monitored more closely for verbal memory challenges and targeted for interventions.

Systemic Review and Meta-analysis of the Intellectual Integrity of Children with Neurofibromatosis Type 1.

BACKGROUND: Cognitive impairment is a common neurologic complication of neurofibromatosis type 1 (NF-1) in childhood. A great number of learning disabilities appear in 30%-65% of children with NF-1. The aim of the study is to compare intelligence quotient (IQ) scores between children with NF-1 and comparable control groups. METHODS: A literature review was conducted using the following databases: Cochrane, PubMed, Wiley, Microsoft Academic, and Google Scholar. We identified 180 papers. The pertinence of any study to the inclusion criteria was determined by assessing the title, key words, and abstracts. Data were extracted using multiple variables that were formulated incongruent with the study aim and then further analyzed. RESULTS: Eleven articles met our criteria, with the highest level of evidence of 3c. A total of 483 NF1 and 443 control participants were included in this meta-analysis. The average and standard deviation of the age was 9.15 ± 3.15 years with an age range of 3.3-18 including 488 male and 438 female. The pooled estimate of the mean difference in all 3 parameters used full-scale IQ, verbal IQ, and performance IQ. Statistically, there was a significantly lower IQ in the NF-1 group compared with the control group with a 95% CI and (P < 0.00001). CONCLUSION: The current meta-analysis illustrated a significant intellectual deficit in children with NF-1 compared with their typically developed peers who were matched by age. Performance IQ was significantly impaired compared with verbal IQ in NF-1 children. The current findings may guide experts to tailor individualized educational programs for children with NF-1.

Adolescents and young adults with neurofibromatosis type 1: A descriptive study of adaptive functioning.

Neurofibromatosis type 1 (NF1) is a genetic syndrome affecting about 1 in 3500 individuals; many of those affected have plexiform neurofibroma (pNF) tumors and associated symptoms and complications. Furthermore, learning and attention problems, as well as deficits in adaptive functioning, are common, often beginning in early childhood. This study aimed to describe adaptive functioning and to examine relationships between adaptive functioning and cognitive and academic variables and level of independence among adolescents and young adults (AYA) with NF1 and pNF tumors. Fifty-five AYA aged 16-31 years participated in a series of neuropsychological evaluations while parents completed the Vineland Adaptive Behavior Scales (VABS-II) as part of a larger natural history study. Over one-third (35%) of AYA were neither in school nor employed. Mean VABS-II daily living and socialization scores were low average while mean Verbal and Performance IQ scores were average. VABS-II scores were positively correlated with processing speed, executive functioning, and working memory scores. Verbal IQ was the only significant predictor of work/school status. Identification of the correlates and predictors of adaptive functioning and life achievement can help guide healthcare providers with the early identification of risk factors and possible areas for intervention.

Attention and Motor Learning in Adult Patients with Neurofibromatosis Type 1.

OBJECTIVE: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that is associated with cognitive disabilities, including attention and motor learning problems. These disabilities have been extensively studied in children with NF1 but limited studies have been performed in adults. METHOD: Attention, motor learning and intellectual performance were studied with neuropsychological tasks in 32 adults with NF1 and 32 controls. RESULTS: The NF1 and control group performed similarly on attention and motor learning tasks, although controls had shorter reaction times than adults with NF1 during the motor learning task (t[60] = -2.20, p = .03). Measures of attention or motor learning were not significantly associated with reduced intellectual performance in NF1. CONCLUSION: In contrast to many studies in children with NF1, our findings did not provide evidence for presence of attention or motor learning problems in adults with NF1 in neuropsychological tasks. Our observations may be of clinical importance to determine treatment focus in adults with NF1.

Role of the parental NF1 carrier in effects of pharmacological inhibition of anaplastic lymphoma kinase in Neurofibromatosis 1 mutant mice.

Neurofibromatosis type 1 (NF1), a genetically determined neurodevelopmental disorder and tumor syndrome, is associated with cognitive impairments, including in executive function and sleep-related problems. Consistent with the human data, NF1 heterozygous (Het) mice show impaired spatial learning and memory in the water maze and extinction of contextual fear memory. It is not clear whether neurological phenotypes might depend on the parental carrier. In this study, we compared the behavioral and cognitive performance of NF1 Het and wild-type litter mates with either the father (PC) or the mother (MC) as the NF1 carrier on a F1 C57BL/66/129SvJ background. The behavioral and cognitive phenotypes and responsiveness to Alk inhibition in heterozygous NF1 offspring depended on whether the parental carrier was maternal or paternal. Alk inhibition (20 mg/kg) increased activity levels during the dark period in NF1 Het PC, but not MC, mice. In the water maze, NF1 Het PC, but not MC, mice showed reduced cognitive flexibility and impaired ability to locate the third hidden platform location, which was improved by Alk inhibition (3.6 mg/kg). Consistent with reduced cognitive flexibility, WT, but not NF1, mice showed better performance in the third than second water maze probe trial. Finally, Alk inhibition (10 mg/kg) increased baseline activity of NF1 MC, but not PC, mice during the fear conditioning test. Thus, the effective dose depends on the behavioral test and genotype but indicates that in NF1 patients cognitive flexibility might be particularly sensitive to Alk inhibition.