Advancing outcome measures in late onset genetic muscle diseases

Abstract

Dysferlinopathy, a type of limb-girdle muscular dystrophy (LGMD) caused by mutations in the DYSF gene, presents with variable patterns of progressive muscle weakness. Outcome measures (OM) of motor performance are used to make clinical care decisions and determine clinical trial outcomes. The lack of a motor performance OM specific to LGMD has limited the understanding of the trajectory and pattern of disease progression and how to best measure a potential response to a novel therapeutic intervention. Multi-centre natural history studies and clinical trials have commenced in this population and therefore there is a critical unmet need for a validated motor performance scale for LGMD.

The aims of this thesis were to analyse existing motor assessment scales for utility in dysferlinopathy, develop a disease specific motor assessment scale, test the scale’s responsiveness in a dysferlinopathy population over one year and investigate the suitability of instrumented gait analysis as an OM in dysferlinopathy.

An international cohort of 193 participants from the Clinical Outcome Study of dysferlinopathy (COS) were assessed six times over three years. After one year, the existing scales were examined for suitability using Rasch analysis and a new scale the North Star Assessment for Dysferlinopathy (NSAD) was developed. The NSAD was validated in the COS population and detected statistically significant change in clinical progression over one year. Furthermore, it correlated with patient reported measures of daily functional ability. Gait analysis demonstrated the ability to differentiate gait patterns when participants walked barefoot or in shoes, and with or without gait aids. Further validation studies in other subtypes of LGMD confirmed suitability of the NSAD for ambulant and non-ambulant patients. The NSAD is the first psychometrically built OM of motor performance specifically designed for LGMD and should be considered for both clinical and research applications.