RNA mis-splicing in children with congenital myotonic dystrophy is associated with physical function

Topic:

Translational Research

Poster Number: P54

Author(s):

Julia Hartman, Center for Inherited Myology Research, Virginia Commonwealth University, Kobe Ikegami, M.S., Center for Inherited Myology Research, Virginia Commonwealth University, Marina Provenzano, PhD, 3Center for Inherited Myology Research, Virginia Commonwealth University, Richmond VA 23298, USA. 4D, Kameron Bates, M.S., Center for Inherited Myology Research, Virginia Commonwealth University, Amanda Butler, DPT, Center for Inherited Myology Research, Virginia Commonwealth University, Aileen Jones, DPT, Center for Inherited Myology Research, Virginia Commonwealth University, Kiera Berggren, SLPT, Center for Inherited Myology Research, Virginia Commonwealth University, Jeanne Dekdebrun, M.S., Neuromuscular Disease Center, University of Rochester, Marnee McKay, PhD, The University of Sydney, Jennifer Baldwin, PhD, The University of Sydney, Kayla Cornett, PhD, The University of Sydney, Joshua Burns, PhD, The University of Sydney, Michael Kiefer, PhD, DPT, Center for Inherited Myology Research, Virginia Commonwealth University, Nicholas E. Johnson, MD PhD, 3Center for Inherited Myology Research, Virginia Commonwealth University, Richmond VA 23298, USA. 4D, Melissa A. Hale, PhD, 3Center for Inherited Myology Research, Virginia Commonwealth University, Richmond VA 23298, USA. 4D

Objectives: Dysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis-splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown.

Methods: Eighty-two participants (42 adults with DM1 and 40 children with CDM) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL]inferred, in skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL]inferred using clinical outcome measures alone. Lastly, we developed regression models to predict 12-month physical function using baseline performance and baseline [MBNL]inferred values.

Results: Myotonia, measured via video of hand opening time (vHOT), was significantly correlated with RNA mis-splicing in our cross-sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis-splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL]inferred in our cohort of all DM1 individuals and when assessing children with CDM independently. Multiple linear regression analyses yielded two models capable of predicting [MBNL]inferred from select clinical outcome assessments alone in all subjects (adjusted r2 = 0.6723) or exclusively in children with CDM (adjusted r2 = 0.5875). MBNL]inferred contributed significantly to the predictive power of our 12-month multiple linear regression models for stair climbing speed. In our cross-sectional cohort of adults and children, baseline stair climbing speed and baseline [MBNL]inferred was able to accurately predict 12-month performance (adjusted r2 = 0.8057).

Interpretation: Our findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL]inferred, in DM1. The strength of these correlations and the development of predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.