P.265Integrating clinical outcome measures, MRI and circulating biomarkers in subjects with Becker muscular dystrophy: a prospective longitudinal study

Abstract

Becker muscular dystrophy (BMD) is caused by mutations in the dystrophin (DMD) gene. BMD is clinically characterized by a highly variable disease course ranging from mild symptoms to severe muscle weakness. Natural history studies in BMD subjects are required to prepare for clinical trials in this population as well as to understand what possible outcomes may be expected in pharmacological interventions aimed at restoring dystrophin expression in subjects affected by Duchenne MD. Until now, most studies have focused on a single or limited set of biomarkers. In the present study, we will present an approach that combines a large number of potential biomarkers to improve prognostic prediction in BMD. In this prospective study we obtained longitudinal and cross-sectional clinical, muscle MRI and serum biomarker data from 52 genetically confirmed BMD subjects with a follow-up of 2 to 8 years. Clinical tests included quantitative muscle assessment of the major muscle groups, the 6-Minute Walk Distance (6-MWD) test, Performance of the Upper Limb (PUL) and the North Star Ambulatory Assessment (NSAA). In a subgroup of 23 subjects, 3-point Dixon MRI scans were acquired and used to calculate weighted average fat fraction and contractile cross-sectional area of the middle of the quadriceps muscle. Serum samples were collected yearly to quantify a panel of biomarkers linked to the pathophysiology such as TGF-β factors, to the metabolic state of muscle such as creatine and creatinine, or to the mutation site (i.e. mutation affecting or not affecting the NOS binding site). Association and integration of the different readouts will be presented including testing on how MRI, clinical and circulating biomarker data can be integrated to improve the prognostic prediction of disease progression in BMD patients. Comparison with DMD patients will also be presented.