Translational research on targeted treatment for cognitive deficits in neurofibromatosis Type 1

Abstract

Neurofibromatosis type 1(NF1) is a common neurocutaneous disorder (birth incidence 1:2000) caused by heterozygous mutations in NF1, a gene on chromosome 17 encoding neurofibromin, which is a suppressor of the Ras pathway. Cognitive dysfunction and behavioural problems are common features of NF1 during childhood. Preclinical studies have shown that excessive inhibition by GABAergic interneurons leads to a deficit in synaptic plasticity, and that statins can reverse the electrophysiological and behavioural problems in Nf1-mice. The overall objective of this thesis is to contribute to the development of medical treatment of the cognitive and behavioural dysfunction in NFl. In chapter 2, we investigated the effect of simvastatin on cognitive performance and behavioural problems in 84 children and adolescents with Neurofibromatosis type 1 in a 12 month randomised placebo­ controlled trial (NF1-SIMCODA). Children and adolescents were treated with 20 mg simvastatin per day (children aged 12 and younger) or 40 mg simvastatin per day (adolescents aged 13 and above). No significant differences between the simvastatin group and the placebo group were observed on the primary outcomes full-scale intelligence, attention problems, or internalising behavioural problems, or on secondary outcomes visual spatial memory, attention, teacher-rated school performance, psychosocial quality of life, self-reported internalising behavioural problems, or fine motor coordination. Conclusively, twelve months of simvastatin treatment did not ameliorate cognitive deficits or behavioural problems in children with NF1.

Another aim of this thesis was to find variables that could explain part of the heterogeneity in clinical features of NFl. Such variables could be important in the selection of patients for clinical trials, or for the planning of subgroup analysis. In chapter 3, we retrospectively analysed a group of 28 children with microdeletion of the NF1 region and compared their disease course during childhood with that of 84 children with intragenic mutations, matched for date-of-birth and gender. We found a higher percentage in the microdeletion-group visiting schools for intellectual disabilities, and a higher number of cutaneous neurofibroma in the microdeletion group at the last moment of follow-up.

These findings are currently being translated in a clinical trial of lamotrigine in adolescents with NFl. In conclusion, despite the neutral results ofthe NF1-SIMCODA trial, a molecularly targeted treatment of cognitive deficits and behavioural problems in NFl still holds promise.