This project proposes a clinical trial in a critical area of need for the neurofibromatosis type 1 (NF1) community. One out of every two children with NF1 is underperforming or failing in school. This frequently leads to decreased educational attainment and reduced opportunities as adults. Behavioral, emotional, and/or learning problems in persons with NF1 are very common. Previous clinical trials to treat NF1 cognitive deficits focused on correcting Ras pathway activation and used outcomes and measurements of behavioral symptoms, which are difficult to quantify. These clinical trials have so far not been successful in providing significant improvements for children with NF1. In this proposal, we are evaluating a novel therapeutic approach and use outcome measurements that may provide significant advantages compared to previous studies, and, therefore, may have a positive impact on children with NF1 and learning difficulties.
In this study, we plan to evaluate whether N-acetylcysteine (NAC), a powerful antioxidant, is safe and effective in the management of abnormal motor and/or learning behaviors in children with NF1. Why an antioxidant? Studies performed in a mouse model of NF1 demonstrated that brain cells called “oligodendrocytes” are very important in the maintenance, balance, and control of an enzyme called nitric oxide synthase (NOS). Treating mice with NAC corrected changes in the brain cells and behavioral abnormalities.
NAC is widely available over the counter and safety data already exist in children. We treated four patients off-label with NAC and observed improved behaviors without side effects. These individuals have remained on NAC for 3 years, and parents report improved school performance. This information from animal models of NF1 along with our uncontrolled clinical observations in children with NF1 suggest that NAC may help improve these complications.
We plan to evaluate the motor system as primary outcome of the trial and validate novel neurophysiology biomarkers for NF1. Motor overflow is a normal developmental step that disappears by late childhood. Children with attention deficit/hyperactivity disorder have abnormal persistence of motor overflow. Children with NF1 showed even more extreme motor overflow when using the validated Physical and Neurological Examination for Subtle Signs (PANESS) scale. For this reason, we propose an evaluation of the motor system, which can be assessed more precisely than behavioral symptoms in children. Behavioral rating scales capture the impressions of parents and teachers in the important domains of home and school, but they are subjective ratings, not brain-based measures. In addition, if treatments during a clinical trial are beneficial, there may be biological changes that precede clinical ones. We are using a novel way to evaluate treatment efficacy by measuring a specific form of brain activity through transcranial magnetic stimulation (TMS). Alterations in this measurement can be quantified in an objective and unbiased way. Our preliminary data in children with NF1 show that TMS measurements are abnormal compared to controls. Finally, we will analyze brain oxidative stress by measuring the antioxidant glutathione using a novel method for detection by magnetic resonance spectroscopy. Quantitative measures of glutathione in the brain will help us determine central nervous system delivery of the NAC antioxidant to children with NF1 and whether this is dose-dependent.
If NAC improves motor behaviors and/or learning in children with NF1, this will be the foundation for a larger study to determine its effectiveness in the general NF1 community. NAC therapy is inexpensive and widely available, so access and clinical implementation will be straightforward for NF1 individuals.
This work will lay the groundwork for future use of relevant biomarkers for treatment and outcomes research for NF1, as well as other biologically similar conditions (“RASopathies”), and ultimately guide development of more effective treatments based on disease pathophysiology.