Neurofibromatosis type 1 (NF1) is a common neurogenetic condition associated with cognitive dysfunction and learning disability. Over the past decade, important and consistent findings have emerged that provide insight into the neurobiological correlates of NF1. In this review, we examine the structural and functional neuroimaging literature in individuals with NF1 and discuss findings that have emerged. Collectively, the studies reviewed here highlight structural and functional brain abnormalities as a feature of NF1 and that these abnormalities contribute to the cognitive impairments that are commonly seen. The most compelling structural finding has been an increase in total brain volume with additional areas of interest including the corpus callosum, cerebral asymmetries and differences in grey and white matter. Although the application of functional neuroimaging techniques in NF1 is in its infancy, early evidence suggests alterations in brain organisation for language and visuospatial function as well as thalamic hypometabolism. Suggestions for future research are discussed, including the importance of addressing specific hypotheses in well-defined subsamples of children with NF1 using appropriate control groups. Identifying the underlying neuropathology of NF1 will be of increased importance as targeted interventions begin to emerge.

Neurofibromatosis type 1 (NF1) is associated with cognitive dysfunction and structural brain abnormalities such as an enlarged corpus callosum. This study aimed to determine the relationship between corpus callosum morphology and cognitive function in children with neurofibromatosis type 1 using quantitative neuroanatomic imaging techniques. Children with neurofibromatosis type 1 (n = 46) demonstrated a significantly larger total corpus callosum and corpus callosum index compared with control participants (n = 30). A larger corpus callosum index in children with neurofibromatosis type 1 was associated with significantly lower IQ, reduced abstract concept formation, reduced verbal memory, and diminished academic ability, specifically reading and math. Our results suggest an enlarged corpus callosum in children with neurofibromatosis type 1 is associated with cognitive impairment and may provide an early structural marker for the children at risk of cognitive difficulties. Cognitive deficits associated with structural brain abnormalities in neurofibromatosis type 1 are unlikely to be reversible and so may not respond to proposed pharmacological therapies for neurofibromatosis type 1-related cognitive impairments.

Summary Mutations of the SCN1A subunit of the sodium channel is a cause of genetic epilepsy with febrile seizures plus (GEFS+) in multiplex families and accounts for 70–80% of Dravet syndrome (DS). DS cases without SCN1A mutation inherited have predicted SCN9A susceptibility variants, which may contribute to complex inheritance for these unexplained cases of DS. Compared with controls, DS cases were significantly enriched for rare SCN9A genetic variants. None of the multiplex febrile seizure or GEFS+ families could be explained by highly penetrant SCN9A mutations.

The rates at which lesions are removed by DNA repair can vary widely throughout the genome, with important implications for genomic stability. To study this, we measured the distribution of nucleotide excision repair (NER) rates for UV-induced lesions throughout the budding yeast genome. By plotting these repair rates in relation to genes and their associated flanking sequences, we reveal that, in normal cells, genomic repair rates display a distinctive pattern, suggesting that DNA repair is highly organized within the genome. Furthermore, by comparing genome-wide DNA repair rates in wild-type cells and cells defective in the global genome-NER (GG-NER) subpathway, we establish how this alters the distribution of NER rates throughout the genome. We also examined the genomic locations of GG-NER factor binding to chromatin before and after UV irradiation, revealing that GG-NER is organized and initiated from specific genomic locations. At these sites, chromatin occupancy of the histone acetyl-transferase Gcn5 is controlled by the GG-NER complex, which regulates histone H3 acetylation and chromatin structure, thereby promoting efficient DNA repair of UV-induced lesions. Chromatin remodeling during the GG-NER process is therefore organized into these genomic domains. Importantly, loss of Gcn5 significantly alters the genomic distribution of NER rates; this has implications for the effects of chromatin modifiers on the distribution of mutations that arise throughout the genome.

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