Neurocutaneous syndromes – including Neurofibromatosis 1 (NF1) and Tuberous Sclerosis Complex (TSC) – are developmental disorders that arise from single gene mutations. Clinically these conditions are associated with tissue overgrowth in multiple organ systems as well as cognitive and behavioral abnormalities. The protein products of the genes mutated in both NF1 and TSC normally function as inhibitors of the AKT/P13K/mTOR signaling pathway, a critical growth pathway whose dysregulation has been implicated in autism as well as several neurodegenerative diseases. The cause of neurocognitive dysfunction in NF1 and TSC is not known, however, the relatively simple genetics of these disorders presents an opportunity to explore gene-behavior relationships in a simplified context that may have relevance for the pathobiology of conditions with more complex genetic associations.
In normal subjects we find that expression of TSC1 and TSC2 (the two genes responsible for TSC) is highest within the human neo-cerebellum and that other related mTOR pathway genes are also selectively over expressed within the cerebellum. Compared to age-matched controls, and accounting for treatment with antiepileptic drugs, we find that children with TSC have increased cerebellar volumes. Interestingly, approximately 50% of children with TSC exhibit behaviors characteristic of autism spectrum disorder (ASD), making tuberous sclerosis one of the most common monogenetic causes of ASD. Considered in this light, our results suggest that the cerebellum may play a central role in TSC pathogenesis and may contribute to the cognitive impairment, including the high incidence of autism spectrum disorder, observed in the TSC population.
In NF1 we find that the volume of specific subcortical regions is much larger in children with NF1 compared to controls. The affected regions are the same as those that commonly exhibit T2 hyperintense signal abnormalities in children with NF1, a qualitative clinical finding characteristic of this disorder. Moreover, these volume differences (like the signal abnormalities) appear to be age dependent in many regions. We also find that NF1 children display significant regional differences in cortical thickness compared to controls, with thinner frontal cortices and thicker occipital cortices, differences that also appear to be age dependent. Finally, through hierarchical cluster analysis, we find that cortical thickness and subcortical volume show distinct patterns of spatial correlation across regions in children with NF1 relative to controls. These systematic morphologic differences may provide a potential biomarker for studying NF1 disease pathophysiology and progression, but will require further characterization through dedicated longitudinal studies.
Overall our TSC and NF1 results suggest a key role for the AKT/P13K/mTOR signaling pathway in the normal development of specific cortical and subcortical structures, and point to the potential importance of circuits connecting subcortical structures with cortical areas –such as the cerebellum and basal ganglia with prefrontal cortex– in the pathophysiology of cognitive dysfunction in these conditions.
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