Inclusion body myopathy (IBM) associated with Paget disease of the bone and frontotemporal dementia or IBMPFD is an autosomal dominant degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. We aim to establish a detailed clinical phenotype of VCP disease amongst 35 (28 affected individuals, 7 presymptomatic gene carriers) individuals versus 14 unaffected first-degree relatives in 14 families to establish useful biomarkers for IBMPFD and identify the most meaningful tests for monitoring disease progression in future clinical trials. Comprehensive studies included the Inclusion Body Myositis Functional Rating Scale (IBMFRS) and fatigue severity scale questionairres, strength measurements using the Manual Muscle Test with Medical Research Council (MRC) scales, hand-held dynamometry using the microFET and Biodex dynamometers, 6 minute walk test (6MWT), and pulmonary function studies. Strong correlation was observed between the IBMFRS and measurements of muscle strength with dynamometry and the other functional tests, indicating that it may be utilized in long-term follow-up assessments due to its relative simplicity. This cross-section study represents the most comprehensive evaluation of individuals with VCP disease to date and provides a useful guide for evaluating and possible monitoring of muscle weakness and pulmonary function progression in this unique cohort of individuals.

This work is dedicated to my parents, Stan and Rita Plewa, who have given so much of their life for me. I hope to one day repay a fraction of the love they have always given me. It is also dedicated to my grandparents, Frank and Carmella Plewa, Peter and Josephine Travalin, who have been my constant source of encouragement. I love them and feel sorrow for the ones that couldn't witness the result of their praise and confidence. They told me I could reach so I did. iii ACKNOWLEDGEMENTS Many people have contributed their help to this work and my education. First I would like to thank my advisors, Dr. Majid Keyhani and Dr. Jay Frankel. Dr. Keyhani taught me what it meant to be a careful researcher and how far I needed to go to become that researcher. He has grown and encouraged hard work and discipline, not just in my research but throughout my life. Dr. Frankel taught me how to think in new ways, how to approach a problem sideways. He also taught me that sometimes you need to relax and laugh at life. Both of my advisors have made me want to ensure they are proud of their student and his work. I would also like to thank my committee member, Dr. Rao Arimilli not only for teaching many of my classes and doing a great deal for my education, but also for his advice. He has helped me find goals and direction. It is a fact that without Dennis Higdon, nothing would ever work in the lab. I thank him for his time, his help, and his insightful thoughts. I appreciate that he is forever willing to lend a hand and some ideas. It is also true that not much would be built without Danny Graham. I thank him for his fabrication skills, excellent advice, and generous loans of tools. I would like to thank my fellow graduate students that I had the great fortune to know during my tenure:

Background: IBMPFD (Inclusion Body Myopathy associated with Paget disease of the bone and Frontotemporal Dementia) is an autosomal dominant inherited disease caused by VCP gene mutations. Very little natural history data exists on this disease. We report a patient with a significant family history of IBMPFD associated with the common R155H mutation in the VCP gene. Objective: This study will address the lack of long-term data for muscle strength, and respiratory function in IBMPFD. The hypothesis is that detailed analysis in a single patient will provide meaningful natural history data in IBMPFD, a progressive neurodegenerative disease. Method: Regression analysis was performed across multiple parameters related to myopathy including dynamometry, MRC scale, IBM functional rating scale, pulmonary function studies and sleep quality. Results: Measurements of this patient highlight progressive generalized weakness in proximal and distal regions, decline in pulmonary function, and asymmetrical strength differences of the upper extremities. Measurements over five years revealed an overall deterioration with a slope of -1.13 and R2 value of 0.77. Conclusion: This unique data derived from long-term evaluations in a patient provides the first report of the rate of progression of muscle weakness and pulmonary function deterioration in VCP associated inclusion body myopathy.