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, placebo-controlled 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 Physical and Neurological Examination for Subtle Signs 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 NAC was generally well tolerated, although two participants were withdrawn by parents because of worsening behavior.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.