Cognitive deficits in children with neurofibromatosis Type I: from recognition to treatment

__Abstract__ Over the past few years, mouse models have significantly contributed to our understanding of the molecular mechanisms underlying cognitive dysfunction in genetic disorders. Moreover, several preclinical studies in mouse models of for instance Neurofibromatosis type 1 (NF1), Tuberous Sclerosis Complex, Down syndrome, Rett syndrome, and Fragile X syndrome have provided evidence that some of these cognitive deficits may be reversible by targeting the underlying molecular disturbances.l-5 These new findings have sparked a great interest in the search for drugs that may be used in patients to ameliorate their cognitive problems.6 A recent study described the beneficial effects of a statin, one of the most widely prescribed classes of medications, on cognitive deficits of a mouse model for NF1.7 This finding offered an exciting and unique opportunity to assess the effect of a drug that has been validated in preclinical studies and for which substantial clinical safety data is available, on cognitive problems in NF1 patients. This thesis focuses on the recognition and treatment of cognitive problems in children with NF1. It aims to provide an overview of the specific aspects of cognitive performance that affect daily life functioning in NF1 children, and tries to identify possible outcome measures that can be used to assess potential therapeutic interventions. This knowledge was used to perform the first randomized, double blind, placebo-controlled trial to assess the effect of statins on cognitive problems in children with NF1