Findings from the Longitudinal CINRG Becker Natural History Study

Abstract

Background: Becker muscular dystrophy is an X-linked, genetic disorder causing progressive degeneration of skeletal and cardiac muscle, with a widely variable phenotype. Objective: A 3-year, longitudinal, prospective dataset contributed by patients with confirmed Becker muscular dystrophy was analyzed to characterize the natural history of this disorder. A better understanding of the natural history is crucial to rigorous therapeutic trials. Methods: A cohort of 83 patients with Becker muscular dystrophy (5–75 years at baseline) were followed for up to 3 years with annual assessments. Muscle and pulmonary function outcomes were analyzed herein. Age-stratified statistical analysis and modeling were conducted to analyze cross-sectional data, time-to-event data, and longitudinal data to characterize these clinical outcomes. Results: Deletion mutations of dystrophin exons 45–47 or 45–48 were most common. Subgroup analysis showed greater pairwise association between motor outcomes at baseline than association between these outcomes and age. Stronger correlations between outcomes for adults than for those under 18 years were also observed. Using cross-sectional binning analysis, a ceiling effect was seen for North Star Ambulatory Assessment but not for other functional outcomes. Longitudinal analysis showed a decline in percentage predicted forced vital capacity over the life span. There was relative stability or improved median function for motor functional outcomes through childhood and adolescence and decreasing function with age thereafter. Conclusions: There is variable progression of outcomes resulting in significant heterogeneity of the clinical phenotype of Becker muscular dystrophy. Disease progression is largely manifest in adulthood. There are implications for clinical trial design revealed by this longitudinal analysis of a Becker natural history dataset.

The First Decade of Journal of Neuromuscular Diseases: Supporting and Advancing the Rapidly Evolving Field of Translational Research

“…Recent trends include an increasing number of publications on outcome measures, biomarkers, clinical trials, natural history, quality of life, and registry studies across a range of neuromuscular diseases. These include well-read and cited publications on splice active antisense oligonucleotides in DMD, use of the stride velocity 95 centile as an EMA-approved outcome measure in DMD, long-term natural history in Becker muscular dystrophy, neurofilament levels as a biomarker in treatment of adults with SMA [12][13][14][15], among others. Going forward we are planning to establish a new feature "clinical trials corner" to respond more quickly to emerging, not fully published results from clinical trials.…”