Decoding Dysfunction in Duchenne Muscular Dystrophy Cardiomyopathy

uchenne muscular dystrophy (DMD) is an X-linked disorder diagnosed in childhood that is characterized by rapidly progressive and life-limiting loss of muscle function.The DMD gene is the largest known gene in humans, comprising 79 exons.Exonic out-of-frame mutations produce truncated or absent dystrophin protein.As a result, cardiac and skeletal myocytes lose their plasma membrane integrity and contractile ability, leading to muscle weakness.DMD affects ≈1 in every 5000 live male births, and these individuals usually die before reaching the third decade of life. 1 With advances in pulmonary and neuromuscular care over the past few decades, DMD cardiomyopathy has emerged as a principal cause of morbidity and mortality in patients with this disease. 2DMD cardiomyopathy is characterized by left ventricular (LV) dysfunction, atrial and ventricular arrhythmias, and a higher mortality than other pediatric dilated cardiomyopathies.Early detection and management are associated with delayed progression of LV dysfunction and with lower mortality.4][5] Genotype-phenotype correlations relating the genetic location of the dystrophin mutation to age of onset of dilated cardiomyopathy have been reported in other dystrophinopathies; however, the associations are less clear in DMD. 6n this issue of Circulation: Genomic and Precision Medicine, Yamamoto et al 7 aim to elucidate relationships between deficiencies in 4 dystrophin tissue-specific isoforms and cardiac dysfunction based on 2-dimensional echocardiographic parameters.The 4 isoforms examined were Dp260, which is expressed in the retina; Dp140, which is expressed in kidney and brain; Dp116, which is expressed in Schwann cells; and Dp71, which is ubiquitously expressed.In this single-center study, the authors retrospectively reviewed 10 years of imaging and laboratory data from 181 male patients diagnosed with DMD as confirmed by genetic testing or immunohistochemical analysis of muscle biopsy.Longitudinal changes in LV ejection fraction and overall cardiac dysfunction-free survival times were consistent with previously reported natural history observations. 2The authors then stratified their analysis by the presence or absence of mutations in particular dystrophin gene isoforms and found that cardiac dysfunction-free survival was higher in those with mutations in the Dp116 isoform compared with those without.Because cardiac Dp116 expression had not been previously reported, the authors performed transcript analysis with reverse transcriptase-polymerase chain reaction and found the presence of Dp116 mRNA in a cardiac sample, leading the authors to posit that this isoform is expressed in cardiomyocytes.The authors concluded that given the observed sharp declines in LV ejection fraction at ages 11 and 26, clinicians should remain vigilant for manifestations of cardiac dysfunction in patients with DMD at these ages.They also hypothesized that suppression of Dp116 expression may Decoding Dysfunction in Duchenne Muscular Dystrophy Cardiomyopathy