Abstract
BackgroundNeurofibromatosis type 1 (NF1) is a monogenic disorder associated with cognitive impairments. In order to understand how mutations in the NF1 gene impact brain structure it is essential to characterize in detail the brain structural abnormalities in patients with NF1. Previous studies have reported contradictory findings and have focused only on volumetric measurements. Here, we investigated the volumes of subcortical structures and the composite dimensions of the cortex through analysis of cortical volume, cortical thickness, cortical surface area and gyrification.MethodsWe studied 14 children with NF1 and 14 typically developing children matched for age, gender, IQ and right/left-handedness. Regional subcortical volumes and cortical gyral measurements were obtained using the FreeSurfer software. Between-group differences were evaluated while controlling for the increase in total intracranial volume observed in NF1.ResultsSubcortical analysis revealed disproportionately larger thalami, right caudate and middle corpus callosum in patients with NF1. Cortical analyses on volume, thickness and surface area were however not indicative of significant alterations in patients. Interestingly, patients with NF1 had significantly lower gyrification indices than typically developing children primarily in the frontal and temporal lobes, but also affecting the insula, cingulate cortex, parietal and occipital regions.ConclusionsThe neuroanatomic abnormalities observed were localized to specific brain regions, indicating that particular areas might constitute selective targets for NF1 gene mutations. Furthermore, the lower gyrification indices were accompanied by a disproportionate increase in brain size without the corresponding increase in folding in patients with NF1. Taken together these findings suggest that specific neurodevelopmental processes, such as gyrification, are more vulnerable to NF1 dysfunction than others. The identified changes in brain organization are consistent with the patterns of cognitive dysfunction in the NF1 phenotype.
Highlights
Neurofibromatosis type 1 (NF1) is a monogenic disorder associated with cognitive impairments
One or more unidentified bright objects (UBOs) were present in 85.7% (12 out of 14) of the children with NF1 distributed as follows: 85.7% (n = 12) of the patients had UBOs in the globus pallidus, 21.4% (n = 3) in the thalami, 14.3% (n = 2) in the corpus callosum, 7.1% (n = 1) in the putamen, 14.3% (n = 2) in the cerebellum and 28.6% (n = 4) had UBOs in the white matter (WM)
The number of UBOs was not correlated with total intracranial volume (r = 0.056, P = 0.850)
Summary
Neurofibromatosis type 1 (NF1) is a monogenic disorder associated with cognitive impairments. Brain development is dependent on a series of complex events including cellular proliferation, growth, differentiation and migration, programmed cell death and synaptic elimination. These events largely determine brain morphology [1]. Neurofibromatosis type 1 (NF1) is a good model in this respect, because it is a monogenic disorder caused by mutations in the NF1 gene. Loss of neurofibromin results in increased cellular growth [10], while it is involved in learning and memory [11]. This disease provides a unique window into gene-brain-behavior relationships. The gross brain anatomy appears normal and it has been difficult to determine if brain structure is altered independent of focal lesions
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