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Background Chronic respiratory failure and heart involvement may occur in Duchenne muscular dystrophy. We aimed to assess the prognostic value of the right ventricular (RV) systolic dysfunction in patients with Duchenne muscular dystrophy. Methods and Results We studied 90 genetically proven patients with Duchenne muscular dystrophy from 2010 to 2019, to obtain respiratory function and Doppler echocardiographic RV systolic function. Prognostic value was assessed in terms of death and cardiac events. The median age was 27.5 years, and median forced vital capacity was at 10% of the predicted value: 83 patients (92%) were on home mechanical ventilation. An RV systolic dysfunction was found in 46 patients (51%). In patients without RV dysfunction at inclusion, a left ventricular systolic dysfunction at inclusion was associated with a higher risk of developing RV dysfunction during follow-up with an odds ratio of 4.5 ( P =0.03). RV systolic dysfunction was significantly associated with cardiac events, mainly acute heart failure (62%) and cardiogenic shock (23%). In a multivariable Cox model, the adjusted hazard ratio was 4.96 (95% CI [1.09-22.6]; P =0.04). In terms of death, we found a significant difference between patients with RV dysfunction versus patients without RV dysfunction in the Kaplan-Meier curves (log-rank P =0.045). Conclusions RV systolic dysfunction is frequently present in patients with Duchenne muscular dystrophy and is associated with increased risk of cardiac events, irrespective of left ventricular dysfunction and mechanical ventilation. Registration URL: https://www.clinicaltrials.org; unique identifier: NCT02501083.

Background: Dystrophinopathies are mostly caused by copy number variations, especially deletions, in the dystrophin gene (DMD). Despite the large size of the gene, deletions do not occur randomly but mainly in two hot spots, the main one involving exons 45 to 55. The underlying mechanisms are complex and implicate two main mechanisms: Non-homologous end joining (NHEJ) and micro-homology mediated replication-dependent recombination (MMRDR)., Objective: Our goals were to assess the distribution of intronic breakpoints (BPs) in the genomic sequence of the main hot spot of deletions within DMD gene and to search for specific sequences at or near to BPs that might promote BP occurrence or be associated with DNA break repair., Methods: Using comparative genomic hybridization microarray, 57 deletions within the intron 44 to 55 region were mapped. Moreover, 21 junction fragments were sequenced to search for specific sequences., Results: Non-randomly distributed BPs were found in introns 44, 47, 48, 49 and 53 and 50% of BPs clustered within genomic regions of less than 700bp. Repeated elements (REs), known to promote gene rearrangement via several mechanisms, were present in the vicinity of 90% of clustered BPs and less frequently (72%) close to scattered BPs, illustrating the important role of such elements in the occurrence of DMD deletions. Palindromic and TTTAAA sequences, which also promote DNA instability, were identified at fragment junctions in 20% and 5% of cases, respectively. Micro-homologies (76%) and insertions or deletions of small sequences were frequently found at BP junctions., Conclusions: Our results illustrate, in a large series of patients, the important role of RE and other genomic features in DNA breaks, and the involvement of different mechanisms in DMD gene deletions: Mainly replication error repair mechanisms, but also NHEJ and potentially aberrant firing of replication origins. A combination of these mechanisms may also be possible.

Background: To explore clinical heterogeneity of Duchenne muscular dystrophy (DMD), viewed as a major obstacle to the interpretation of therapeutic trials, Methodology/principal Findings: A retrospective single institution long-term follow-up study was carried out in DMD patients with both complete lack of muscle dystrophin and genotyping. An exploratory series (series 1) was used to assess phenotypic heterogeneity and to identify early criteria predicting future outcome; it included 75 consecutive steroid-free patients, longitudinally evaluated for motor, respiratory, cardiac and cognitive functions (median follow-up: 10.5 yrs). A validation series (series 2) was used to test robustness of the selected predictive criteria; it included 34 more routinely evaluated patients (age>12 yrs). Multivariate analysis of series 1 classified 70/75 patients into 4 clusters with distinctive intellectual and motor outcomes: A (early infantile DMD, 20%): severe intellectual and motor outcomes; B (classical DMD, 28%): intermediate intellectual and poor motor outcome; C (moderate pure motor DMD, 22%): normal intelligence and delayed motor impairment; and D (severe pure motor DMD, 30%): normal intelligence and poor motor outcome. Group A patients had the most severe respiratory and cardiac involvement. Frequency of mutations upstream to exon 30 increased from group A to D, but genotype/phenotype correlations were restricted to cognition (IQ>71: OR 7.7, 95%CI 1.6-20.4, p<0.003). Diagnostic accuracy tests showed that combination of "clinical onset <2 yrs" with "mental retardation" reliably assigned patients to group A (sensitivity 0.93, specificity 0.98). Combination of "lower limb MMT score>6 at 8 yrs" with "normal or borderline mental status" reliably assigned patients to group C (sensitivity: 1, specificity: 0.94). These criteria were also predictive of "early infantile DMD" and "moderate pure motor DMD" in series 2., Conclusions/significance: DMD can be divided into 4 sub-phenotypes differing by severity of muscle and brain dysfunction. Simple early criteria can be used to include patients with similar outcomes in future therapeutic trials.

Background: Impulse-conduction abnormalities and arrhythmias are common in myotonic dystrophy (MD). This study was performed to determine whether a correlation exists between electrophysiological (EP) testing data and clinical status, heart function, or size of the DNA abnormality (cytosine-thymine-guanine sequence repeat)., Methods and Results: Eighty-three MD patients underwent invasive EP studies prompted primarily by the presence of asymptomatic conduction abnormalities. AV conduction disturbances were common and mainly distal (HV interval, 66.2+/-14 ms). AV conduction observed from the surface ECG was generally concordant with endocardial measurements. However, 11 of 20 patients with normal surface ECGs had abnormal subhisian conduction. Atrial arrhythmias were inducible in 41% of cases and correlated with prolongation of the AH interval (P=0.02) and a shorter atrial refractory period (P=0.04). Induction of ventricular arrhythmias (18%) correlated strongly with age (P=0. 0003). After adjustment for age, the extent of DNA mutation correlated with the Walton score (P=0.0018) but not with conduction abnormalities or induction of arrhythmias., Conclusions: Prolongation of the HV interval is the most common conduction abnormality in MD and can be reliably recognized only by invasive EP testing. It raises the issue of prophylactic pacing to limit the incidence of sudden death in MD. Atrial and ventricular arrhythmias are often inducible, although their predictive value remains to be determined. Young age emerged as the most powerful predictor of inducible ventricular tachyarrhythmias. Conversely, we found no relationship between ECG or EP abnormalities recorded during invasive testing and the DNA mutation size or severity of peripheral muscle involvement.

In a series of 100 patients exhibiting clinical and molecular features of facioscapulohumeral muscular dystrophy (FSHMD), five patients had conduction defects or arrhythmia in the absence of cardiovascular risk factors--namely, intraventricular conduction delay and supraventricular arrhythmia induced by electrophysiologic investigations (two patients), palpitations associated with supraventricular arrhythmia (one patient), severe atrioventricular block leading to pacemaker implantation (one patient), and ventricular tachycardia related to arrhythmogenic right ventricular cardiomyopathy (one patient). Patients with FSHMD may have cardiac involvement.

Myopathy may be associated with very variable cardiac involvement, the expression of which is related to the type of neuromuscular disease and also to the individual. This retrospective study, performed between 1986 and 1991, was undertaken to determine the prevalence of cardiac involvement in myopathy. A total of 216 subjects with an average age of 34 years were reviewed by clinical examination, ECG, echocardiography and Holter ECG monitoring. Some patients also underwent complementary radionuclide (scintigraphy, angiography) and electrophysiological investigations. The results confirmed cardiac disease in over a half of patients. Although 3/4 of the patients were asymptomatic from the cardiac point of view at the time of evaluation, the severity of certain lesions led to a number of specific therapeutic interventions. This suggests that simple, non-invasive cardiac diagnostic procedures should be undertaken systematically in the early stages of myopathic disease.

The prevalence and prognostic value of ventricular arrhythmias were examined in 45 Duchenne muscular dystrophy patients without congestive heart failure and followed up for 3 yr. Baseline evaluation included 24 h ECG monitoring, systolic time intervals measurement (preejection period/left ventricular ejection time PEP/LVET), echocardiogram and vital capacity tests. Fifteen patients (33%) had ventricular premature beats (VPB > or = 2 h-1). More complex ventricular ectopy (Lown grades 3, 4A, 4B) occurred in 12 patients (27%), who had abnormal ventricular contractility (PEP/LVET > 0.48) and an area of akinesia or dyskinesia. Complex VPB were present on presentation in only 3 of the 30 survivors (10%) but were detected in 6 of the 15 patients (40%) who died. Patients who died suddenly were more likely to have had documented complex ventricular arrhythmias (6 of 9; 66%). It is concluded that: (1) significant arrhythmias frequently coexist with asymptomatic left ventricular dysfunction and wall motion abnormalities; (2) complex VPB as well as left ventricular dysfunction and dilated cardiomyopathy are risk factors for sudden death.

The purpose of this study was to evaluate the prevalence of latent cardiac heart failure in Duchenne's muscular dystrophy (DMD). Systolic time intervals (STI) were measured in a cross-sectional study of a group of 177 patients 6-21 years old. Total electromechanical systole (QS2), left ventricular ejection time (LVET), and pre-ejection period (PEP), were corrected for heart rate by means of regression equations obtained from 33 normal subjects (QA2 I, LVET I, PEP I). Mean STI values were significantly different from those observed in an age-matched control group. PEP I was prolonged, LVET I was abbreviated, while QS2 I remained unaltered. STI varied significantly with age. Abnormal values were uncommon before age 10 years. The most critical period was 14-16 years, with an abrupt increase in prevalence from 35 to 72%. Such changes point to the practical use of the STI for clinical decision making especially for surgery.