A Review of Psychological, Social, and Behavioral Functions in the RASopathies

Walsh, Karin S.; Castillo, Allison Del; Kennedy, Tess; Karim, A.; Semerjian, Claire

doi:10.1007/s40817-020-00088-1

Cited by 5 publications

(5 citation statements)

References 81 publications

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“…Indeed, circumscribed interests, together with compulsions and rituals, have been found to positively correlate with IQ in autistic children [ 79 ], although some studies have shown no association or only small positive associations between IQ and IS behaviours [ 75 – 77 ]. It is also interesting to consider how common NF1 characteristics such as executive deficits [ 80 ] and anxiety [ 81 ] may affect the expression of IS behaviours in NF1, since these constructs conceptually converge and have overlapping symptom presentations (e.g. cognitive/behavioural inflexibility).…”

Section: Discussionmentioning

confidence: 99%

Delineating the autistic phenotype in children with neurofibromatosis type 1

et al. 2022

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Background Existing research has demonstrated elevated autistic behaviours in children with neurofibromatosis type 1 (NF1), but the autistic phenotype and its relationship to other neurodevelopmental manifestations of NF1 remains unclear. To address this gap, we performed detailed characterisation of autistic behaviours in children with NF1 and investigated their association with other common NF1 child characteristics. Methods Participants were drawn from a larger cross-sectional study examining autism in children with NF1. The population analysed in this study scored above threshold on the Social Responsiveness Scale-Second Edition (T-score ≥ 60; 51% larger cohort) and completed the Autism Diagnostic Interview-Revised (ADI-R) and/or the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2). All participants underwent evaluation of their intellectual function, and behavioural data were collected via parent questionnaires. Results The study cohort comprised 68 children (3–15 years). Sixty-three per cent met the ADOS-2 ‘autism spectrum’ cut-off, and 34% exceeded the more stringent threshold for ‘autistic disorder’ on the ADI-R. Social communication symptoms were common and wide-ranging, while restricted and repetitive behaviours (RRBs) were most commonly characterised by ‘insistence on sameness’ (IS) behaviours such as circumscribed interests and difficulties with minor changes. Autistic behaviours were weakly correlated with hyperactive/impulsive attention deficit hyperactivity disorder (ADHD) symptoms but not with inattentive ADHD or other behavioural characteristics. Language and verbal IQ were weakly related to social communication behaviours but not to RRBs. Limitations Lack of genetic validation of NF1, no clinical diagnosis of autism, and a retrospective assessment of autistic behaviours in early childhood. Conclusions Findings provide strong support for elevated autistic behaviours in children with NF1. While these behaviours were relatively independent of other NF1 comorbidities, the importance of taking broader child characteristics into consideration when interpreting data from autism-specific measures in this population is highlighted. Social communication deficits appear similar to those observed in idiopathic autism and are coupled with a unique RRB profile comprising prominent IS behaviours. This autistic phenotype and its relationship to common NF1 comorbidities such as anxiety and executive dysfunction will be important to examine in future research. Current findings have important implications for the early identification of autism in NF1 and clinical management.

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Section: Discussionmentioning

confidence: 99%

Delineating the autistic phenotype in children with neurofibromatosis type 1

et al. 2022

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“…Association tracts are key for social processes including mentalizing and empathy 18,19 and deficits in social processes are highly prevalent in NS and NF1. 20,21 Furthermore, the extent of the effect of NS and NF1 along these tracts is unclear. That is, whether white-matter microstructure is compromised along the entirety of the tract or localized at specific segments.…”

Section: Introductionmentioning

confidence: 99%

Impact of Pathogenic Variants of the Ras-MAPK Pathway on Major White Matter Tracts in the Human Brain

Siqueiros-Sanchez,

Dai,

McGhee

et al. 2024

Preprint

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Noonan syndrome (NS) and Neurofibromatosis type-1 (NF1) are genetic conditions linked to pathogenic variants in genes of the Ras-MAPK signaling pathway. Both conditions hyperactivate signaling of the Ras pathway and exhibit a high prevalence of neuropsychiatric disorders. Further, animal models of NS and NF1 and human imaging studies show white-matter abnormalities in both conditions. While these findings suggest Ras pathway hyper-activation effects on white-matter, it is unknown whether these effects are syndrome-specific or pathway-specific. To characterize the effect of NS and NF1 on human white-matter microstructural integrity and discern potential syndrome-specific influences on microstructural integrity of individual tracts, we collected diffusion-weighted imaging data from children with NS (n=24), NF1 (n=28), and age and sex-matched controls (n=31). We contrasted the clinical groups (NS or NF1) and controls using voxel-wise, tract-based, and along-tract analyses. Outcomes included voxel-wise, tract-based and along-tract fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD). NS and NF1 showed similar patterns of reduced FA and increased AD, RD, and MD on white-matter relative to controls and different spatial patterns. NS presented a more extensive spatial effect than NF1 on white-matter integrity as measured by FA. Tract-based analysis also demonstrated differences in effect magnitude with overall lower FA in NS compared to NF1 (d=0.4). At the tract-level, NS specific-effects on FA were detected in association tracts (superior longitudinal, uncinate and arcuate fasciculi; p's<0.012) and NF1 specific-effects were detected in the corpus callosum (p's<0.037) compared to controls. Results from along-tract analyses aligned with results from tract-based analyses and indicated that effects are pervasive along the affected tracts. In conclusion, we find that pathogenic variants in the Ras-MAPK pathway are associated with white-matter abnormalities as measured by diffusion in the developing brain. Overall NS and NF1 show common effects on FA and diffusion scalars, as well as specific unique effects, namely on temporoparietal-frontal tracts (intra-hemispheric) in NS and on the corpus callosum (inter-hemispheric) in NF1. The observed specific effects not only confirm prior observations from independent cohorts of NS and NF1 but also inform on syndrome-specific susceptibility of individual tracts. Thus, these findings suggest potential targets for precise, brain-focused outcome measures for existing medications, such as MEK inhibitors, that act on the Ras pathway.

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“…Thus, the aim of the present study was to assess the risks for psychiatric disorders in a population-based cohort of 905 individuals with NF1 and 7614 population comparisons using data from comprehensive nationwide registries. As having emotional, social or behavioral difficulties can have a major impact on quality of life and daily living skills, early diagnosis and intervention is needed to improve the life of individuals with NF1 and psychiatric comorbidity (Walsh et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Beside a high risk for physical complications (Kenborg et al, 2020), many individuals with NF1 also experience cognitive impairments (Rosser & Packer, 2003). A recently published review of psychological, social, and behavioral functions in the RASopathies summarized that children with NF1 have social difficulties, but also impairments in the emotional and behavioral functioning (Walsh et al, 2020). Previous studies have found a high prevalence of neurodevelopmental disorders, including autism spectrum disorders (ASD) and attention‐deficit/hyperactivity disorders (ADHD) in children with NF1 (Garg et al, 2013), but also co‐occurrence between symptoms of ASD and ADHD (Morris et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Psychiatric disorders in individuals with neurofibromatosis 1 in Denmark: A nationwide register‐based cohort study

Kenborg

Andersen

Duun‐Henriksen

et al. 2021

American J of Med Genetics Pt A

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The aim of this study was to assess the risks of psychiatric disorders in a large cohort of 905 individuals with NF1 and 7614 population comparisons matched on sex and year of birth. The cohort was linked to the Danish Psychiatric Central Research Register to ascertain information on hospital contacts for psychiatric disorders based on the International Classification of Diseases version 8 and 10. The hazard ratio (HR) for a first psychiatric hospital contact was higher in girls (4.19, 95% confidence interval [CI] 1.81-9.69) and boys with NF1 (5.02, 95% CI 3.27-7.69) <7 years of age than in the population comparisons. Both sexes had increased HRs for developmental disorders, including attention deficit/hyperactivity disorders, autism spectrum disorders, and intellectual disabilities in childhood. Females with NF1 had also increased HRs for unipolar depression, other emotional and behavioral disorders, and severe stress reaction and adjustment disorders in early adulthood. The HRs for psychoses,

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A Review of Psychological, Social, and Behavioral Functions in the RASopathies

Cited by 5 publications

References 81 publications

Delineating the autistic phenotype in children with neurofibromatosis type 1

Delineating the autistic phenotype in children with neurofibromatosis type 1

Impact of Pathogenic Variants of the Ras-MAPK Pathway on Major White Matter Tracts in the Human Brain

Psychiatric disorders in individuals with neurofibromatosis 1 in Denmark: A nationwide register‐based cohort study

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