Understanding the Biology of a Rare Genetic Disease

Duchenne muscular dystrophy (DMD) is a devastating inherited disorder that causes muscle wasting in boys. Symptoms begin early in childhood (around 3-5 years old) and progress quickly. Those afflicted with DMD are usually wheelchair-bound by their teens and often die from heart or lung failure by their mid-20s.

DMD is caused by mutations in the gene that produces dystrophin, a connective protein that strengthens muscle fibers. Although the genetic cause of DMD has been known for over 30 years, we still do not fully understand how loss of dystrophin leads to muscle deterioration.

There is no cure for DMD and monitoring disease progression and drug response in clinical trials is difficult. The primary measure in most trials is the six-minute walking distance which excludes very young children as well as older patients who can no longer walk. More accurate and objective measures of DMD are essential for assessing efficacy and speeding FDA approval of new therapies.

To identify biomarkers for DMD, the SOMAscan assay was used to measure protein levels in serum samples from Duchenne patients and age-matched healthy controls. Forty-four proteins showed significant changes (24 increased and 20 decreased) in patients with DMD. The proteins link to disease processes such as muscle fiber leakage, fibrosis, inflammation and muscle degeneration.

Many of the DMD protein markers were at their highest levels in the youngest patients and then decrease with age as muscles atrophy. These results suggest that significant muscle damage is occurring at a very early age (before 4 years). Protein measurements could offer a minimally invasive way of monitoring DMD during infancy, when interventions are likely to have the biggest impacts.

In a study published in 2018, Italian researchers re-analyzed the previously published SOMAscan assay data to identify 52 proteins that were significantly different in the DMD patients, of which 27 had been identified in the previous study. The researchers found that only six of the proteins were needed to diagnose DMD with 100% accuracy. Using previously developed computational methods to see how proteins relate to one another, they identified several biological processes and functions that are dysregulated in DMD. In addition to demonstrating how rich SOMAscan data are (and how they can be continuously mined for new insights), this study further expands our molecular understanding of DMD, which is essential for developing effective treatments.

Hathout, Y et al. (2015) “Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy.” Proc Natl Acad Sci U S A 112(23): 7153-7158.

Parolo, S et al. (2018) “Combined use of protein biomarkers and network analysis unveils deregulated regulatory circuits in Duchenne muscular dystrophy.” PLoS One 13(3): e0194225.