New Models Help Us Better Understand Disease Progression in Dysferlinopathy

A new study led by researchers at the John Walton Muscular Dystrophy Research Centre and published in Neurology: Genetics provides fresh insight into how muscle degeneration progresses over time in individuals with dysferlinopathy (LGMD R2), a form of limb-girdle muscular dystrophy.

The research team analysed three years of quantitative MRI data from 109 individuals enrolled in the Dysferlinopathy Clinical Outcome Study (COS), an international natural history study funded by the Jain Foundation. Using statistical models, the team tracked the fat fraction (FF) – a measure of how much muscle tissue has been replaced by fat – in the lower limb muscles over time.

Key Findings

• Lower leg muscles tend to be more affected earlier in the disease, especially before the age of 30, while thigh muscles show a steeper progression and become more severely involved later on.

• Muscles that perform similar movements tend to deteriorate at a similar pace, suggesting that biomechanics may play a key role in disease progression.

• Age at symptom onset, and sex (in the lower legs) were relevant predictors of disease severity.

• Women showed higher fat fraction values in the lower leg muscles compared to men, even though other functional scores have historically suggested better physical performance.

• While the multivariate models helped better explain disease progression at a group level, individual variability remained high, highlighting the need to include other factors in future studies – such as lifestyle, comorbidities, and genetics beyond the DYSF gene.

This modelling work offers a more detailed picture of how dysferlinopathy evolves, and can support the design of future clinical trials by helping researchers choose better-matched participant groups and outcome measures. Although all patients experience muscle degeneration, this study shows that not all muscles progress at the same rate, and that personal factors – like age of onset and sex – matter. The previously mentioned findings reinforce the importance of considering these differences when planning future clinical trials.

Access the paper here: https://www.neurology.org/doi/10.1212/NXG.0000000000200283