A randomized, double-blind, pilot study of N-acetylcysteine for motor and cognitive symptoms in youth with Neurofibromatosis type 1

Background: Children and youth with Neurofibromatosis type 1 (NF1) commonly experience motor, behavioral, and cognitive problems.Promising findings from an NF1 mouse model suggested that the antioxidant N-acetylcysteine (NAC) might address underlying mechanistic deficits. Methods:We conducted a 12-week (8-week treatment, 4-week washout), double-blind, placebocontrolled randomized trial of NAC in 8-16-year-olds with NF1.We screened 481 children, identified 203 eligible, and randomized 25; 23 received at least one dose (10 NAC at ~70 mg/kg/day; 13 placebo).Outcomes were safety, tolerability, motor function (primary: Physical and Neurological Examination for Subtle Signs), cognitive function (secondary: Attention Deficit/Hyperactivity Disorder symptom scores and executive function measures), and exploratory biomarkers (Transcranial Magnetic Stimulation and Magnetic Resonance Spectroscopy measures).Results: In the modified intention to treat analysis, no significant difference in PANESS was observed between groups.In completer-analyses, NAC did not improve any secondary or exploratory outcome at 8 weeks.NAC was generally well tolerated, although two participants were withdrawn by parents because of worsening behavior.Test-retest reliability of scales, measures, and biomarkers over 12 weeks was generally moderate.Conclusions: NAC was generally well tolerated but did not improve motor or behavioral outcomes in youth with NF1.Larger, longer trials with preceding dose-escalation and target-engagement studies are needed to evaluate new therapies.