- Genetic and Epigenetic Differences in Monozygotic Twins with NF1
- Neurofibromatosis Clinical Trials Consortium
- Improving Cognitive and Behavioral Function in NF1 Genetically Engineered Mice
- Defining Quality of Life in NF2
Identification of genes or other factors that modify NF1 could enable clinicians to identify patients who are at an increased risk of serious complications from the disorder. Differences in clinical symptoms and severity have even been documented in twins with NF1, suggesting that non-inherited factors are involved. Dr. Schorry, with funding from an FY09 Exploration - Hypothesis Development Award, is examining copy number variants (CNVs), genetic changes that may occur after conception, in identical twins with differing NF1 symptom severity. Eleven pairs of identical twins have been enrolled in the study and analysis of CNVs within twin pairs has been performed. Twins were found to have a mean of 18.9 raw CNVs per individual, with a mean of 3.4 CNVs containing genes. Deletion CNVs were more common than duplications. Preliminary analysis did not identify any discordant CNVs in the 11 twin sets analyzed and the number of CNVs was not significantly different within twin pairs. A large duplication CNV on chromosome 17q was noted as a possible modifier for a severe tumor burden phenotype. Several genes in close proximity to reported CNVs were found to merit further study for potential effects on NF1 phenotype. Dr. Schorry has received ancillary funding from Dr. Nancy Ratner's National Institutes of Health award to sequence the NF1 gene in this cohort of twins to look for associations of specific genotypes with NF1 manifestations. This study represents an important step in the identification of NF1 biomarkers and therapeutic targets.
Individuals suffering from neurofibromatosis type 1 (NF1) may develop neurofibromas, malignant peripheral nerve sheath tumors (MPNST), skeletal dysplasia, cognitive disorders, or low-grade gliomas. Individuals with NF2 develop vestibular schwannomas, often resulting in deafness, and other tumors such as meningiomas and epenymomas. Those with schwannomatosis develop multiple schwannomas and severe pain. The severity of NF-related complications in affected individuals is extremely variable, and current therapies are unable to eradicate symptoms. Therefore, the identification of effective NF therapies is greatly needed. The Neurofibromatosis Clinical Trials Consortium (NFCTC) was established in 2006 to accelerate clinical trials for children and adults with significant complications of NF. Over the last 5 years, with funding from the NFRP, the NFCTC has conducted clinical trials investigating treatments for NF1 complications including plexiform neurofibromas, cognitive disorders, low-grade gliomas, and MPNST. With support from the NFRP in FY11, the NFCTC will continue its mission. The Consortium has expanded to include 13 member sites as well as four additional collaborating sites to improve geographical coverage and inclusion of adults and children with all forms of NF. In addition, the NFCTC will broaden its focus to include NF2 and schwannomatosis alongside NF1 in performing clinical trials.
Neurofibromatosis Type 1 (NF1), which results from a mutation of the NF1 gene, predisposes individuals to tumor growth along nerves resulting in pain, loss of function in the area of the affected nerve, or difficulty with movement. Approximately two-thirds of children affected with NF1 experience learning disabilities and attention-deficit disorder (ADD), limiting their performance in school. Additionally, NF1 children may experience further cognitive disability resulting from the cancer treatments used to treat optic gliomas, a type of brain tumor that is common in NF1. Dr. David Gutmann at Washington University, a recipient of a fiscal year 2009 Investigator-Initiated Research Award from the Neurofibromatosis Research Program (NFRP), is hoping to expand the understanding of NF1-associated learning disorders using a genetically engineered mouse model of NF1 in which the mice develop optic gliomas.
Characterization of the NF1 mouse model revealed behavior and attention deficits similar to those observed in children with NF1. In addition, Dr. Gutmann confirmed that NF1 mutant mice had reduced levels of the neurotransmitter dopamine, which has a variety of functions including roles in cognition, attention, learning, and memory. With funding from the NFRP, he demonstrated that the deficit in dopamine in NF1 mutant mice can be reliably detected using positron emission tomography (PET), establishing a non-invasive method to monitor dopamine in live animals. To demonstrate that the NF1 mutant mouse model can be used as a therapeutic drug testing platform, Dr. Gutmann measured NF1 mouse behavior and dopamine levels using PET following administration of the ADD medication methylphenidate or L-Deprenyl, which increases dopamine levels in the brain. Treatment with either of these agents corrected the attention deficit seen in NF1 mutant mice and returned dopamine levels, measured by PET, to those of normal mice. Dr. Gutmann's work suggests that there may be a subset of children with NF1-associated learning disabilities that may respond more favorably to dopamine-targeted therapies, and these children could be identified using non-invasive PET imaging techniques.
Neurofibromatosis Type 2 (NF2) is a genetic disorder characterized by the development of bilateral vestibular schwannomas, benign tumors of the nerve that transmits sensory information from the inner ear to the brain. NF2 patients are also at risk for developing other types of nervous system tumors, cataracts, and skin tumors. While these tumors are non-malignant, tumor growth may result in loss of hearing and balance, ringing in the ears, headache, abnormal sensation and vision, as well as more life-threatening symptoms based on the location of tumor. The clinical management of NF2 is complex and controversial as therapeutic interventions may also lead to significant nerve damage and dysfunction. NF2 experts agree that patient quality of life (QoL) is an important consideration in clinical decision-making; however, no NF2-specific QoL scales are available. Dr. Maura Cosetti received a fiscal year 2010 Postdoctoral Traineeship Award from the Neurofibromatosis Research Program to address this need. During this traineeship, Dr. Cosetti will develop, refine, and validate a multi-dimensional metric to evaluate QoL in NF2 patients. Beginning with a literature review of existing QoL metrics and structured interviews with NF2 clinicians and patients, Dr. Cosetti will develop a QoL questionnaire that will address the unique concerns of the NF2 population. This questionnaire will be refined and further validated in a larger cohort of NF2 patients, and results will be compared to clinical outcome measures and other QoL measurements. Dr. Cosetti's disease-specific, validated QoL metric will be used to inform NF2 patient treatment, evaluate treatment outcomes, and standardize results across clinical trials.