Abstract

To provide individualized estimates of expected child neuropsychiatric and neuroanatomical outcomes by using parent cognitive and behavioral traits in a predictive framework.Predictive modeling was applied to 52 families of children with Noonan syndrome, a neurogenetic syndrome affecting the Ras/mitogen-activated protein kinase (MAPK) pathway.Parent cognition (specifically visuospatial and motor abilities), depression, anxiety, and attention-deficit/hyperactivity disorder symptoms were significantly associated with child outcomes in these domains. Parent cognition was also significantly associated with child neuroanatomical variability. The middle temporal cortex was weighted strongly in the model predicting child neuroanatomy and not identified in previous work, but was correlated with parent cognition, suggesting a larger familial effect in this region.Using parent traits provides a more individualized estimate of expected child cognitive, behavioral, and neuroanatomical outcomes. Understanding how parent traits influence neuroanatomical outcomes helps to further a mechanistic understanding of the impact of Ras/MAPK on neurodevelopmental outcomes. Further refinement of predictive modeling to estimate individualized child outcomes will advance a precision medicine approach to treating Noonan syndrome, other neurogenetic syndromes, and neuropsychiatric disorders more broadly.

View details for DOI 10.1111/dmcn.16278

View details for PubMedID 40119877

View details for Web of Science ID 001434801700212

Abstract

Evidence suggests pathological roles of myelination in neurodevelopmental disorders, but our understanding is limited. We investigated quantitative T1 mapping (QT1) as a clinically feasible tool for measuring myelination in children with neurodevelopmental disorders of the RAS-MAPK signaling pathway (RASopathies).We collected QT1, diffusion-weighted, and structural MRI scans from 72 children (49 RASopathies, 23 typical developing (TD)). QT1 measures of myelin content included the macromolecular tissue volume (MTV) in white matter and R1 (1/T1 relaxation) of the cortex. For white matter, we assessed between-groups differences across 39 tracts. For cortical R1, we used principal components analysis to reduce dimensionality and capture myelination patterns across 360 regions. A multivariate ANOVA assessed differences across principal components. Finally, a support vector machine (SVM) identified the most discriminative features between TD and RASopathies.Thirty-four of 39 tracts were higher in MTV in RASopathies relative to TD (pFDR <.05), indicating widespread elevation in myelination. Our MANOVA revealed a group effect on cortical R1 (p=.002, η2 =.028), suggesting cortical myelination differences between-groups. SVM yielded an accuracy of 87% and identified cognitive and cortical R1 features as the most discriminant between-groups.We found widespread elevated myelin in white matter tracts and region-dependent patterns of cortical myelination in children with RASopathies. QT1 enabled us to leverage preclinical models showing oligodendrocyte dysfunction to uncover the myelination pattern in vivo in the developing human brain. Using QT1, myelin represents a promising treatment target that can be identified and monitored in neurodevelopmental disorders, offering significant potential for advancing current therapeutic strategies.

View details for DOI 10.1101/2025.02.25.25322881

View details for PubMedID 40061352

View details for PubMedCentralID PMC11888482

Abstract

Rasopathies, including Noonan Syndrome (NS) and Neurofibromatosis type 1 (NF1), are developmental disorders caused by germline mutations in genes of the RAS/mitogen-activated protein kinase pathway (RAS-MAPK). This study investigates irritability, a highly prevalent transdiagnostic construct, in children with Rasopathies and the impact of Rasopathy status on the associations between irritability, emotional dysregulation-related disorders, and social skills impairments. The sample comprise 174 children aged 4-17 (age mean = 9.49; 98 females), including 113 children with Rasopathies (NS n = 85, NF1 n = 28) and 61 age-sex-matched typically developed (TD) children. We used parent questionnaires (CBCL, SRS) to assess irritability, symptoms of ADHD, defiance, anxiety/depression, and social skills impairments while controlling for cognitive measures (IQ). Children with Rasopathies exhibited higher irritability than TD children (mean difference = 1.09; p < 0.001). Children with NS showed a weaker association between irritability and ADHD symptoms compared to TD children (p = .032, etap 2 = .03) and a stronger association between irritability and social skills impairments compared to both TD (p = .033, etap 2 = .03), and NF1 groups (p = .009, etap 2 = .06). We present novel and clinically significant findings showing high irritability in children with Rasopathies. Our study provides syndrome-specific results, suggesting differences in the mechanisms involved in irritability, ADHD, and social processes in children with NS and NF1. In essence, children with Rasopathies showed a highly irritable profile associated with ADHD symptoms and social skills impairments, with a significantly stronger association between irritability and social processes in NS. Our results suggest that developing prevention and treatments targeting irritability can distinctly affect the trajectories of neurodevelopmental disorders in children with Rasopathies.

View details for DOI 10.21203/rs.3.rs-5428038/v1

View details for PubMedID 39764141

View details for Web of Science ID 001407851100218

Abstract

Noonan syndrome and neurofibromatosis type 1 are genetic conditions linked to pathogenic variants in genes of the Ras-mitogen-activated protein kinase signalling pathway. Both conditions hyper-activate signalling of the Ras-mitogen-activated protein kinase pathway and exhibit a high prevalence of neuropsychiatric disorders. Further, animal models of Noonan syndrome and neurofibromatosis type 1 and human imaging studies show white matter abnormalities in both conditions. While these findings suggest Ras-mitogen-activated protein kinas pathway hyper-activation effects on white matter, it is unknown whether these effects are syndrome-specific or pathway-specific. To characterize the effect of Noonan syndrome and neurofibromatosis type 1 on human white matter's microstructural integrity and discern potential syndrome-specific influences on microstructural integrity of individual tracts, we collected diffusion-weighted imaging data from children with Noonan syndrome (n = 24), neurofibromatosis type 1 (n = 28) and age- and sex-matched controls (n = 31). We contrasted the clinical groups (Noonan syndrome or neurofibromatosis type 1) and controls using voxel-wise, tract-based and along-tract analyses. Outcomes included voxel-wise, tract-based and along-tract fractional anisotropy, axial diffusivity, radial diffusivity and mean diffusivity. Noonan syndrome and neurofibromatosis type 1 showed similar patterns of reduced fractional anisotropy and increased axial diffusivity, radial diffusivity, and mean diffusivity on white matter relative to controls and different spatial patterns. Noonan syndrome presented a more extensive spatial effect than neurofibromatosis type 1 on white matter integrity as measured by fractional anisotropy. Tract-based analysis also demonstrated differences in effect magnitude with overall lower fractional anisotropy in Noonan syndrome compared to neurofibromatosis type 1 (d = 0.4). At the tract level, Noonan syndrome-specific effects on fractional anisotropy were detected in association tracts (superior longitudinal, uncinate and arcuate fasciculi; P < 0.012), and neurofibromatosis type 1-specific effects were detected in the corpus callosum (P < 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-mitogen-activated protein kinase pathway are associated with white matter abnormalities as measured by diffusion in the developing brain. Overall, Noonan syndrome and neurofibromatosis type 1 show common effects on fractional anisotropy and diffusion scalars, as well as specific unique effects, namely, on temporoparietal-frontal tracts (intra-hemispheric) in Noonan syndrome and on the corpus callosum (inter-hemispheric) in neurofibromatosis type 1. The observed specific effects not only confirm prior observations from independent cohorts of Noonan syndrome and neurofibromatosis type 1 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-mitogen-activated protein kinase pathway.

View details for DOI 10.1093/braincomms/fcae274

View details for PubMedID 39210910

View details for PubMedCentralID PMC11358645