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Neurobiology of Disease In Children: Neurofibromatosis


Victoria, British Columbia, Canada
October 16, 2001



Statement of Symposium Goals (15 min)
Bernard Maria

Current Approaches to Diagnosis and Molecular Testing
Moderator: Peggy Wallace

Clinical Manifestations and Diagnostic Criteria (30 min)
Jan Friedman

The NF1 Gene and Genetics (30 min)
Dave Viskochil

NF1 Mutations and Molecular Testing (20 min)
Peggy Wallace

Question and Answer Session


Clinical Manifestations in Context of Pathogenesis
Moderator: Bruce Korf

Neurofibromas and Optic Pathway Gliomas in NF1 (40 min)
Roger Packer

Neurofibromin is a Tumor Suppressor (30 min)
David Gutmann

Mouse Models of NF1 (30 min)
Karen Cichowski

Question and Answer Session


Cognitive Aspects of NF1
Moderator: Kathryn North

Learning Disabilities and ADHD in NF1 (30 min.)
Kathryn North

NF1 Gene Expression in Neuroglia (30 min.)
David Gutmann

Cognitive Deficits in the NF1 Mouse (30 min)
Alcino Silva



Current Therapies and Clinical Trials
Moderator: Roger Packer

Farnesylation Inhibitors (20 min.)
Jay Gibbs

Antiangiogenesis (20 min.)
Bob Martuza

Natural History Studies (20 min)
Bruce Korf


Future Prospects for NF1 Research and Therapy
Moderators: Bob Finkelstein and Giovanna Spinella


Closing Comments (10 min)
Bernard Maria



Workshop Summary

This is an exciting time for neurofibromatosis research. During the past decade, researchers isolated the genes that cause the two forms of neurofibromatosis, developed increasingly sophisticated animal models, and learned a great deal about the molecular mechanisms that underlie neurofibromatosis 1 and neurofibromatosis 2. Most importantly, these advances are beginning to suggest potential therapies for these often devastating disorders. These leaps forward were the result not only of the efforts of a talented community of neurofibromatosis researchers but also of the tireless work of advocacy groups working to facilitate and focus research efforts.

The neurofibromatosis workshop held in conjunction with the 30th annual meeting of the Child Neurology Society in Victoria, British Columbia, was a remarkable event. The meeting focused on neurofibromatosis 1, the more prevalent form of the disease. It brought a panel of top neurofibromatosis researchers, clinicians, and patient advocates together with an audience of pediatric neurologists. This was a unique opportunity for researchers to update clinicians regarding their recent discoveries and for clinicians to discuss specific problems that arise in treating patients with neurofibromatosis. In the following sections, I will highlight future research directions suggested at the meeting.


Basic Research

Molecular Mechanisms

The development of rational therapeutics for neurofibromatosis 1 will require a greater understanding of the molecular mechanisms underlying this disease. Although significant strides have been made toward understanding the structure and function of the NF1 gene (also known as neurofibromin), a great deal remains to be learned. For example, the function of a large portion of the neurofibromin protein is completely unknown, and the roles of its different isoforms are not clearly understood. Although it is clear that neurofibromin regulates the Ras signaling pathway, the potential involvement of other signal transduction pathways (e.g., the protein kinase A cascade) is only beginning to be elucidated. Finally, the variable expressivity of the neurofibromatosis 1 phenotype in patients suggests that additional modifier genes have yet to be identified. Genetic studies using the mouse and fruit fly will be critical to achieving this goal and may help identify additional therapeutic targets.

The situation is particularly complex because of the multiple problems different patients with neurofibromatosis 1 experience. For example, although progress has been made toward identifying the regions of neurofibromin important for cognitive function, the mechanisms that lead to learning disabilities, tumor formation, bone abnormalities, and other symptoms are still obscure. To elucidate these mechanisms, it will be critical to determine the role of the NF1 gene in Schwann cells, astrocytes, neurons, and other cell types.

Animal Models and Technological Strategies

Several investigators discussed the use of animal models and other approaches toward understanding the pathogenesis of neurofibromatosis 1. There is a critical need for more "refined" mouse models of this disease. Different laboratories have begun creating mice in which the NF1 gene is disrupted in specific cell types and/or during specific time windows. Such mice will be essential for understanding the function of neurofibromin in specific tissues and the effect of NF1 loss on the expression of potential downstream genes. Because malignant neurofibromatosis 1?associated tumors likely result from a combination of genetic alterations, investigators are modeling the development of these tumors by creating mice in which multiple genes (e.g., NF1 and P53) are introduced or disrupted. The various mouse strains being developed will serve as critical tools not only for understanding neurofibromatosis 1 but also ultimately for testing candidate therapeutics.

Another strategy discussed at the meeting was the use of micro array analysis. By comparing gene expression profiles in NFIdeficient (i.e., heterozygous or homozygous) and normal cells, additional targets for potential therapeutic intervention may be identified. It will be important to perform such analyses in multiple cell types that may contribute to the neurofibromatosis 1 phenotype.


Clinical Research

Diagnosis and Natural History

Neurofibromatosis 1 can be diagnosed using National Institutes of Health (NIH) Diagnostic Criteria, which include specific clinical features and the existence of a family member with the disease. However, because approximately half of all cases are sporadic, diagnosis can be difficult. This is particularly true for young children with no family history of neurofibromatosis 1. In such patients, molecular analysis of the NFI gene can be useful. Current technologies permit a success rate as high as 95% in detecting existing mutations that affect the sequence of the NFl protein or the splicing of its ribonucleic acid.

The importance of natural history studies, which are currently under way, was emphasized at the meeting. Neurofibromatosis 1related tumors often grow slowly, and their progress is currently unpredictable. As mentioned earlier, patients with neurofibromatosis 1 also can exhibit a variety of other symptoms, including learning disabilities, scoliosis, vasculopathy, and growth retardation. The success of clinical trials will depend on selecting as treatment end points clinical features whose progress in the absence of therapeutic intervention is known. Better understanding of the possible clustering of symptoms also will be invaluable for predicting the course of the disease and determining optimal treatment strategies.


Workshop participants described the obstacles that currently block the design of rational clinical trials for neurofibromatosis 1. In addition to the need for more natural history data, many questions need to be addressed. For example, which neurofibromatosis 1related tumors should serve as an appropriate target for therapeutic intervention? Because plexiform neurofibromas are the major cause of morbidity in patients with neurofibromatosis 1, they are obvious targets for clinical trials. Should the goal of future trials be to reduce tumor load or to prevent further tumor growth? How will tumor size and number be measured? Should learning disabilities, which affect a large fraction of patients with neurofibromatosis 1, be a major target of clinical trials? To what extent should other symptoms be assessed in such trials? Should molecular genetic parameters be used to determine which patients are included for treatment? What quality?of?life measures should be incorporated into trials? As potential treatments are developed, these and other issues will need to be resolved.

Although clinical trials of new drugs represent the future for progress in treating neurofibromatosis 1, it is imperative that we not ignore the present. At the workshop, several speakers discussed the efficacy of currently available diagnostic tools and treatments. Members of the audience discussed the merits of diagnostic magnetic resonance imaging evaluation with the panelists, and the advantages and disadvantages of radiation therapy, surgery, and other interventions were explored. In one interesting talk, the speaker speculated about how neurofibromatosis 1 might be diagnosed and treated in the year 2020, both with respect to chronic and episodic features of the disease.


Final Comments

Although current treatments for neurofibromatosis 1 are woefully inadequate, the future holds real promise for the development of more effective therapies. Through a combination of further basic research, translational research, and clinical trials, it is only a matter of time before strategies that are more effective and less invasive are developed. An important theme that emerged at several points during this workshop was that neurofibromatosis 1 research will benefit greatly from research involving other disorders (e.g., cancers, learning disabilities). For example, many of the drugs being developed to treat various cancers are possible candidates for evaluation in fixture neurofibromatosis clinical trials. An equally important theme is that neurofibromatosis research will have tremendous implications for understanding basic biologic processes relevant to many other diseases. It was clear from this workshop that neurofibromatosis research is shifting from primarily basic studies to a combination of basic, translational, and clinical investigation. Meetings such as this one will be important for facilitating communication between neurofibromatosis researchers and the patients they ultimately serve.

From: Journal of Child Neurology, Volume 17, Number 8, August 2002. This issue of the Journal of Child Neurology features a series of articles prepared by conference participants and the transcript of the conference's question?and?answer sessions, panel discussions, and open discussions.


Last Modified April 12, 2011