Research in Congenital Muscle Disease

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Over the past year, I continued as an Assistant Clinical Investigator in the Tissue Injury Branch of the NINR, a position I started in September of 2012. Over the past year, I have enrolled participants in three active protocols. The first one is a study to develop the first proxy motor outcome assessment in young children with neuromuscular disease, entitled Development of a Proxy Motor Outcome Measure in Young Children with Neuromuscular Disease. Last year, we completed all necessary qualitative phone interviews for Aim 1 of the protocol. We transcribed and analyzed these interviews to uncover their main themes. This analysis was followed by an in-person focus group of expert clinicians to further analyze the interview transcriptions and to develop common themes relevant for the questionnaire, related to motor function. This year, all parents who participated in the interviews were informed about these themes and our projected domains for the questionnaire and their feedback was welcomed. The themes were used to create the items for the new scale. After the items were developed, the same focus group of experts was queried an initial rounds of emailing, using the Delphi method, to finalize the items on the new scale. Two to three more rounds of emailing will follow. The goal is to use the new scale in future clinical trials to decrease parent stress related to travel to research centers for clinical trials and to improve ecological validity of motor function by utilizing parent insight in the home setting. My team also enrolled 70 participants to date in the second active protocol, The Calibration and Validation of the PROMIS and Neuro-QOL Questionnaires in Cerebral Palsy and Congenital Muscular Dystrophy. Preliminary item response theory analyses are underway with Columbia University, the collaborating institution, to validate these two questionnaires for use in neuromuscular disease patients. A third study, which received the Bench to Bedside Award, obtained IRB approval this past winter. This is a clinical trial of antioxidant therapy in patients with RYR1 congenital myopathy, and 22 patients have been enrolled since March 2015. This summer, the postdoc I hired last year for this trial mentored 2 summer students and 1 special volunteer, who analyzed the data on the 10 first patients' baseline visit. We identified some preliminary correlations between cardiopulmonary exercise testing, arterial occlusion with near infrared spectroscophy, forced vital capacity, and the six minute walk test. We also identified changes with age on muscle ultrasound in specific muscle groups in these patients. My postdoc and I are writing a review of the literature on RYR1 and its interacting proteins. I am also an Associate Investigator on an NINDS protocol entitled Clinical and Molecular Manifestations of Neuromuscular and Neurogenetic Disorders of Childhood. As part of this protocol, I took a 5-year project with me from NINDS when left NINDS and started with NINR. The project was a 5-year study of clinical outcome measures in two subtypes of congenital muscular dystrophy, Collagen VI-Related Myopathy and Laminin 2 Related Muscular Dystrophy. In June of 2014, I organized the 5th and final year of the study with my research team, a postbac fellow, a research nurse, and two summer students, including a nursing student and a doctor of pharmacy student. A first author manuscript summarizing the first two-year pilot study of this 5-year longitudinal was published in Neuromuscular Disorders. A manuscript focusing on forced vital capacity in these 2 disease subtypes has been submitted. Four manuscripts are in preparation: one describing the validation of several upper extremity measures in this population, one describing the validation of the ActiGraph accelerometer in this population, one describing the validation of the PedsQoL in this population, and one describing sensitivvity to change of the main outcome measures over the entire 5 years. Manuscripts published this past year include: Zukosky, K., Meilleur, K.G., Dastgir, J., Medne, L., Devoto, M., Collins, J., Rooney, J., Zou, Y., Yang, M., Johnson, J., Gibbs, J.R., Finkel, R., Elman, L., Felice, K., Ferguson, T., Tennekoon, G., Traynor, B., Bnnemann, C.G. (2015). Novel ACTA1 mutation identified by exome sequencing underlies a progressive scapuloperoneal myopathy. JAMA Neurology. DOI: 10.1001/jamaneurol.2015.37. Meilleur, K.G., Jain, M.S., Hynan, L.S., Shieh, C.Y., Kim, E., Waite, M., McGuire, M., Fiorini, C., Glanzman, A.M., Main, M., Rose, K., Duong, T., Bendixen, R., Linton, M.M., Arveson, I.C., Nichols, C., Yang, K., Fischbeck, K.H., Wagner, K.R., North, K., Mankodi, A., Grunseich, C., Hartnett, E.J., Smith, M., Donkervoort, S., Schindler, A., Kokkinis, A., Leach, M.E., Foley, A.R., Collins, J., Muntoni, F., Rutkowski, A., Bnnemann, C.G. (2014). Results of a Two-Year Pilot Study of Clinical Outcome Measures in Collagen VI-related Myopathy and LAMA2-related Muscular Dystrophy. Neuromuscul Disord Sept 28 doi:10.1016/j.nmd.2014.09.010.