Ellen Plasschaert

Prevalence of Autism Spectrum Disorder symptoms in children with neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic condition. While considerable work has focused on cognitive functioning, several research groups also observed difficulties in social functioning as a prominent feature of NF1. These problems and the possible link between NF1 and Autism Spectrum Disorder (ASD) have become increasingly important in recent NF1 literature. The aim of the current study was to assess ASD characteristics in a hospital‐based NF1 pediatric population (n = 82) using the standardized Children Social Behavior Questionnaire (CSBQ) and Social Responsiveness Scale (SRS) to account for the prevalence, severity, and nature of social problems. In a parallel study, comprehensive ASD assessment was performed in a subgroup of NF1 children with a strong suspicion of ASD (n = 31). Results indicate that NF1 children have more social problems than typical controls, more frequently reported above 8 years. The SRS shows that 63% is at risk of ASD symptoms. According to item analyses, most problems were observed on items measuring orientation in, understanding of and being tuned onto a social situation (CSBQ) and social cognition and communication (SRS). In the parallel study, 27 NF1 children were diagnosed with ASD. These children have a distinct phenotype compared to a heterogeneous ASD group, with pronounced social–communicative impairments and fewer restrictive/repetitive behaviors. This study provides a better understanding of social problems in NF1 and the phenotypical overlap with ASD symptomatology. Despite their willingness to engage with others, NF1 children with or without ASD encounter various difficulties in their social–communicative life.

Characterizing the microstructural basis of "unidentified bright objects" in neurofibromatosis type 1: A combined in vivo multicomponent T2 relaxation and multi-shell diffusion MRI analysis.

Introduction The histopathological basis of “unidentified bright objects” (UBOs) (hyperintense regions seen on T2-weighted magnetic resonance (MR) brain scans in neurofibromatosis-1 (NF1)) remains unclear. New in vivo MRI-based techniques (multi-exponential T2 relaxation (MET2) and diffusion MR imaging (dMRI)) provide measures relating to microstructural change. We combined these methods and present previously unreported data on in vivo UBO microstructure in NF1. Methods 3-Tesla dMRI data were acquired on 17 NF1 patients, covering 30 white matter UBOs. Diffusion tensor, kurtosis and neurite orientation and dispersion density imaging parameters were calculated within UBO sites and in contralateral normal appearing white matter (cNAWM). Analysis of MET2 parameters was performed on 24 UBO–cNAWM pairs. Results No significant alterations in the myelin water fraction and intra- and extracellular (IE) water fraction were found. Mean T2 time of IE water was significantly higher in UBOs. UBOs furthermore showed increased axial, radial and mean diffusivity, and decreased fractional anisotropy, mean kurtosis and neurite density index compared to cNAWM. Neurite orientation dispersion and isotropic fluid fraction were unaltered. Conclusion Our results suggest that demyelination and axonal degeneration are unlikely to be present in UBOs, which appear to be mainly caused by a shift towards a higher T2-value of the intra- and extracellular water pool. This may arise from altered microstructural compartmentalization, and an increase in ‘extracellular-like’, intracellular water, possibly due to intramyelinic edema. These findings confirm the added value of combining dMRI and MET2 to characterize the microstructural basis of T2 hyperintensities in vivo.

Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1: A Study of the International NF1-ASD Consortium Team (INFACT)

Importance Recent reports have demonstrated a higher incidence of autism spectrum disorder (ASD) and substantially elevated autistic trait burden in individuals with neurofibromatosis type 1 (NF1). However, important discrepancies regarding the distribution of autistic traits, sex predominance, and association between ASD symptoms and attentional problems have emerged, and critical features of the ASD phenotype within NF1 have never been adequately explored. Establishing NF1 as a monogenic cause for ASD has important implications for affected patients and for future research focused on establishing convergent pathogenic mechanisms relevant to the potential treatment targets for ASD. Objective To characterize the quantitative autistic trait (QAT) burden in a pooled NF1 data set. Design, Setting, and Participants Anonymized, individual-level primary data were accumulated from 6 tertiary referral centers in the United States, Belgium, United Kingdom, and Australia. A total of 531 individuals recruited from NF1 clinical centers were included in the study. Main Outcomes and Measures Distribution of ASD traits (Social Responsiveness Scale, second edition [SRS-2], with T scores of ≥75 associated with a categorical ASD diagnosis); attention-deficit/hyperactivity disorder (ADHD) traits (4 versions of Conners Rating Scale, with T scores of ≥65 indicating clinically significant ADHD symptoms); ASD symptom structure, latent structure, base rate derived from mixture modeling; and familiality. Results Of the 531 patients included in the analysis, 247 were male (46.5%); median age was 11 years (range, 2.5-83.9 years). QAT scores were continuously distributed and pathologically shifted; 13.2% (95% CI, 10.3%-16.1%) of individuals scored within the most severe range (ie, above the first percentile of the general population distribution) in which the male to female ratio was markedly attenuated (1.6:1) relative to idiopathic ASD. Autistic symptoms in this NF1 cohort demonstrated a robust unitary factor structure, with the first principal component explaining 30.9% of the variance in SRS-2 scores, and a strong association with ADHD symptoms (r = 0.61). Within-family correlation for QAT burden (intraclass correlation coefficient, 0.73 in NF1-affected first-degree relatives) exceeded that observed in the general population and ASD family samples. Conclusions and Relevance This study provides confirmation that the diversity of mutations that give rise to NF1 function as quantitative trait loci for ASD. Moreover, the within-family correlation implicates a high degree of mutational specificity for this associated phenotype. Clinicians should be alerted to the increased frequency of this disabling comorbidity, and the scientific community should be aware of the potential for this monogenic disorder to help elucidate the biological features of idiopathic autism.

Observations on intelligence and behavior in 15 patients with Legius syndrome

Legius syndrome is a RAS‐MAPK syndrome characterized by pigmentary findings similar to neurofibromatosis type 1 (NF1), but without tumor complications. Learning difficulties and behavioral problems have been reported to be associated with Legius syndrome, but have not been studied systematically. We investigated intelligence and behavior in 15 patients with Legius syndrome and 7 unaffected family members. We report a mean full‐scale IQ of 101.57 in patients with Legius syndrome, which does not differ from the control group. We find a significantly lower Performance IQ in children with Legius syndrome compared to their unaffected family members. Few behavioral problems are present as assessed by the Child Behavior Checklist (CBCL) questionnaire. Our observations suggest that, akin to the milder somatic phenotype, the cognitive phenotype in Legius syndrome is less severe than that of NF1.

Behavioral and cognitive outcomes for clinical trials in children with neurofibromatosis type 1

Objective: To evaluate the appropriateness of cognitive and behavioral outcome measures in clinical trials in neurofibromatosis type 1 (NF1) by analyzing the degree of deficits compared to reference groups, test-retest reliability, and how scores correlate between outcome measures. Methods: Data were analyzed from the Simvastatin for cognitive deficits and behavioral problems in patients with neurofibromatosis type 1 (NF1-SIMCODA) trial, a randomized placebo-controlled trial of simvastatin for cognitive deficits and behavioral problems in children with NF1. Outcome measures were compared with age-specific reference groups to identify domains of dysfunction. Pearson r was computed for before and after measurements within the placebo group to assess test-retest reliability. Principal component analysis was used to identify the internal structure in the outcome data. Results: Strongest mean score deviations from the reference groups were observed for full-scale intelligence (−1.1 SD), Rey Complex Figure Test delayed recall (−2.0 SD), attention problems (−1.2 SD), and social problems (−1.1 SD). Long-term test-retest reliability were excellent for Wechsler scales (r > 0.88), but poor to moderate for other neuropsychological tests (r range 0.52–0.81) and Child Behavioral Checklist subscales (r range 0.40–0.79). The correlation structure revealed 2 strong components in the outcome measures behavior and cognition, with no correlation between these components. Scores on psychosocial quality of life correlate strongly with behavioral problems and less with cognitive deficits. Conclusions: Children with NF1 show distinct deficits in multiple domains. Many outcome measures showed weak test-retest correlations over the 1-year trial period. Cognitive and behavioral outcomes are complementary. This analysis demonstrates the need to include reliable outcome measures on a variety of cognitive and behavioral domains in clinical trials for NF1.

Executive functioning deficits in children with neurofibromatosis type 1: The influence of intellectual and social functioning

The aim of this study was to provide a broad picture of Executive Functioning (EF) in NF1 children, while taking into account their lower average IQ and increased Autism Spectrum Disorder (ASD) symptoms. This was done by administering an extended battery of tasks and questionnaires, designed to reduce task impurity, that measures five EF domains (inhibition, cognitive flexibility, working memory, generativity and planning) in a laboratory setting and in daily life. Data are presented for 42 age‐ and gender‐matched NF1, 52 typically developing, and 52 ASD children (8–18 years). Our results indicated that although EF is highly influenced by IQ and severity of ASD symptoms, EF deficits seem to be a core feature of NF1 and not merely a secondary effect of a lower IQ and/or increased ASD symptoms. However, additional research is needed to confirm these findings.

Deficient motor timing in children with neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is one of the most common single-gene disorders affecting fine and visual-motor skills. This case-control study investigated motor timing as a possible related performance deficit in children with NF1. A visual-motor reaction time (VRT) test was administered in 20 NF1 children (mean age 9 years 7 months) and 20 age- and gender-matched typically developing (TD) children. Copying and tracing performance were evaluated using the Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI). Children with NF1 responded with an increased reaction time (RT) to temporally predictive stimuli compared to TD children, whereas RT at unpredictive stimuli did not differ between groups. Motor timing indexed by the RT decrease at predictive stimuli significantly associated with the Beery VMI copy and tracing outcomes. Deficient motor timing as an actual symptom may add to further research on the pathogenesis of NF1-associated motor impairment and the development of more effective treatment.

Choroidal abnormalities in café‐au‐lait syndromes: A new differential diagnostic tool ?

The best known café‐au‐lait syndrome is neurofibromatosis type 1 (NF1). Legius syndrome (LS) is another, rarer syndrome with café‐au‐lait macules (CALMs). In young patients their clinical picture is often indistinguishable. We investigated the presence of choroidal abnormalities in syndromes with CALMs as a candidate tool for a more efficient diagnosis.

Visuoperceptual processing in children with neurofibromatosis type 1: True deficit or artefact?

Impairments in visuoperceptual processing have long been considered a hallmark deficit of individuals with Neurofibromatosis type 1 (NF1). However, it is unclear which specific visuoperceptual subprocesses are impaired and whether impairments on these tasks really result from visuoperceptual impairments or rather from confounding factors like Executive Functioning (EF) impairments, lower intelligence (IQ) and/or co‐occurring symptoms of Autism Spectrum Disorder (ASD). To answer these questions, we administered four visuoperceptual tasks and two control tasks in 39 children with NF1, 52 typically developing children and 52 children with ASD (8–18 years), all matched for age and gender. Furthermore, EF, IQ, and symptoms of ASD were assessed. Children with NF1 displayed intact visual form discrimination and intact information integration along the dorsal visual pathway. Moreover, their reduced performance on a task requiring integration of information along the ventral visual stream and their more detail‐oriented processing style appeared to result from confounding EF impairments and not from visuoperceptual impairments per se. The co‐occurring ASD symptoms and lower IQ of the children with NF1 did not impact substantially upon their visuoperceptual performance. These findings point to the large impact of EF impairments on the performance of visuoperceptual task and suggest that individuals with NF1 show intact visual form discrimination, intact visual integration, and typical visual processing style when potential confounding factors are controlled for. This may have large repercussions for the interpretation of other findings on visuoperceptual processing in individuals with NF1.