Chesshyre M, Ridout D, Hashimoto Y, Ookubo Y, Torelli S, Maresh K, Ricotti V, Abbott L, Gupta VA, Main M, Ferrari G, Kowala A, Lin YY, Tedesco FS, Scoto M, Baranello G, Manzur A, Aoki Y, Muntoni F.

J Cachexia Sarcopenia Muscle. 2022 Apr;13(2):1360-1372. doi: 10.1002/jcsm.12914. Epub 2022 Jan 26. PMID: 35083887; PMCID: PMC8977977.

Lay summary

Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by progressive muscle weakness. The primary cause of DMD is the absence or deficiency of a protein called dystrophin. However, there are multiple isoforms of the dystrophin protein, mostly or exclusively produced in the brain, and their specific roles in motor function have never been studied. 

The paper titled “Investigating the Role of Dystrophin Isoform Deficiency in Motor Function in Duchenne Muscular Dystrophy” explores how different mutations in the dystrophin gene which affects in a different way the brain dystrophin isoforms, contribute to motor function in individuals with DMD. 

The team identified first different group of boys with DMD whose DMD mutation was expected to impact on only one isoform produced in brain; or 2 isoforms, or three isoforms. They then went on to correlate the site of the dystrophin mutation with the motor skills. 

The findings of the study revealed that the presence or absence of specific dystrophin isoforms in individuals with DMD clearly correlated with variations in motor function. Children only missing a single isoform had milder muscle weakness and better motor performance, while those missing all the brain isoforms were characterised by poorer motor abilities. 

These results provide insights into the complex relationship between dystrophin isoforms including the isoforms present in the brain and motor function in DMD. Understanding the specific roles of different dystrophin isoforms can help explain the variability in motor abilities observed among individuals with DMD, something that we observed in the daily clinical practice. 

By elucidating the connection between dystrophin isoforms produced in the brain and motor function, this study opens up possibilities for better understanding the response to therapeutic intervention DMD. These results in particular will be very important to plan therapeutic intervention especially in the very young boys with DMD as the expectation of therapeutic response might be different in different group of boys, depending on the site of their mutation and how this affects the production of the brain isoforms. 

This work demonstrated for the first time a clear relationship between how brain function also controls muscle function in boys with DMD. The identification of specific brain isoforms associated with varying motor abilities provides valuable insights into the heterogeneity of the disease and offers potential avenues for targeted interventions. By better understanding the role of dystrophin isoforms, researchers can strive towards more personalized and effective treatment strategies for individuals living with DMD.