In many forms of muscular dystrophy, including Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), weakness and degeneration of the cardiac muscle can be a major part of the disease, and one that frequently shortens life. In this study coordinated by Federica Montanaro at Nationwide Children's Hospital, scientists have identified specific mutations in the dystrophin gene that predict whether cardiomyopathy will occur earlier or later in the course of BMD. They studied the dystrophin gene mutations and the clinical medical records of 78 people with either X-linked dilated cardiomyopathy or BMD-associated cardiomyopathy. They found that different mutations could cause the median age at the onset of cardiomyopathy to range from the mid-20s to the mid-40s. Previous studies have found that mutations in the dystrophin gene that affect the rod domain usually cause relatively mild skeletal muscle degeneration, compared to mutations that affect either end of the dystrophin protein outside the rod domain. The new findings show that mutations in the rod domain can have unexpectedly severe effects on the ability of dystrophin to protect the heart muscle. The researchers found that patients with dystrophin mutations and cardiomyopathy, with or without skeletal muscle involvement, had mutations affecting the rod domain or the actin-binding domain. Those with mutations in exons 45 to 49 that affected the rod domain and preserved hinge 3 had a median age of onset of cardiomyopathy of either 26 or 36 years, depending on whether the mutation disrupted the dystrophin protein structure. Those with mutations in exons 45 to 55 that affected the rod domain but did not preserve hinge 3 had a median age of onset of cardiomyopathy of 43 years. The median age of onset for cardiomyopathy for those with mutations in exons 2 to 9, affecting the actin-binding domain, was 23. These data will allow better prediction of cardiomyopathy in BMD and earlier consideration of cardioprotective treatments in this disease. In addition, the results provide insight into which parts of the dystrophin protein are essential to preserve when miniaturized versions of the dystrophin gene or shortened dystrophin protein molecules are being considered as therapeutic strategies.

Références : Analysis of dystrophin deletion mutations predicts age of cardiomyopathy onset in becker muscular dystrophy.
Circ Cardiovasc Genet. 2009 Dec;2(6):544-51.