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Duchenne and Becker muscular dystrophy severity depends upon the nature and location of the DMD gene lesion and generally correlates with the dystrophin open reading frame. However, there are striking exceptions where an in-frame genomic deletion leads to severe pathology or protein-truncating mutations (nonsense or frame-shifting indels) manifest as mild disease. Exceptions to the dystrophin reading frame rule are usually resolved after molecular diagnosis on muscle RNA. We report a moderate/severe Becker muscular dystrophy patient with an in-frame genomic deletion of DMD exon 5. This mutation has been reported by others as resulting in Duchenne or Intermediate muscular dystrophy, and the loss of this in-frame exon in one patient led to multiple splicing events, including omission of exon 6, that disrupts the open reading frame and is consistent with a severe phenotype. The patient described has a deletion of dystrophin exon 5 that does not compromise recognition of exon 6, and although the deletion does not disrupt the reading frame, his clinical presentation is more severe than would be expected for classical Becker muscular dystrophy. We suggest that the dystrophin isoform lacking the actin-binding sequence encoded by exon 5 is compromised, reflected by the phenotype resulting from induction of this dystrophin isoform in mouse muscle in vivo. Hence, exon skipping to address DMD-causing mutations within DMD exon 5 may not yield an isoform that confers marked clinical benefit. Additional studies will be required to determine whether multi-exon skipping strategies could yield more functional dystrophin isoforms, since some BMD patients with larger in-frame deletions in this region have been reported with mild phenotypes.

Introduction Mutations in the 79 exons of the dystrophin gene result in muscle wasting and weakness of varying clinical severity, ranging from severe/typical Duchenne muscular dystrophy (DMD) to intermediate DMD and mild Becker muscular dystrophy (BMD), depending on the frameshift of the mutation. We previously reported that males with DMD have progressively declining appendicular lean mass (ALM) and ALM index (ALMI) with age and worsening functional motor ability compared with healthy controls. These indices have not been studied in patients with intermediate DMD and BMD phenotypes and across DMD genotypes. In this study, we compared age‐related trajectories of ALM and ALMI of patients who had (1) BMD without functional mobility deficits with patients who had DMD at different stages of disease and healthy controls; (2) a DMD intermediate phenotype with patients who had a typical DMD phenotype; and (3) DMD categorized by genotype. Methods We conducted a retrospective review of ALM and ALMI data from 499 patients (ages 5–23 years) with DMD (466 typical and 33 intermediate) and 46 patients (ages 5–21 years) with BMD (without functional mobility deficits and functional mobility score of 1). Patients were grouped according to age reflecting disease stage (ages 5 to <7, 7 to <10, 10 to <14, and 14 to <20 years) and genotype (mutations in exons 1–30, 31–44, 45–62, and 63–79). Results ALM and ALMI trajectories of patients with BMD paralleled those of healthy controls until adolescence, in contrast to patients with DMD. ALMI Z‐scores of patients with BMD remained within ±2 SD without decline while those of patients with DMD fell below −2 SD around age 12 years. Patients with BMD had increasing ALM and ALMI with age, with peak accrual between ages 10 to <14 years. ALMI declined after age 14 years for those with intermediate DMD compared with 10 years for patients with typical DMD. Patients with mutations in exons 63–79 had a greater decline in ALMI as compared with those with other genotypes after age 10 years. Conclusions Age‐related changes in ALMI in patients with BMD and intermediate DMD differ from those with typical DMD, reflecting their clinical phenotypes. ALM and ALMI should be further studied in patients with BMD and DMD subtypes for their potential value as surrogate markers to characterize the severity of BMD and DMD and inform clinical care decisions and clinical trial designs.

Duchenne and Becker muscular dystrophies are caused by mutations in dystrophin. Cardiac manifestations vary broadly, making prognosis difficult. Current dystrophin genotype–cardiac phenotype correlations are limited. For skeletal muscle, the reading-frame rule suggests in-frame mutations tend to yield milder phenotypes. We performed dystrophin genotype–cardiac phenotype correlations using a protein-effect model and cardiac magnetic resonance imaging. A translational model was applied to patient-specific deletion, indel, and nonsense mutations to predict exons and protein domains present within truncated dystrophin protein. Patients were dichotomized into predicted present and predicted absent groups for exons and protein domains of interest. Development of myocardial fibrosis (represented by late gadolinium enhancement [LGE]) and depressed left ventricular ejection fraction (LVEF) were compared. Patients (n = 274) with predicted present cysteine-rich domain (CRD), C-terminal domain (CTD), and both the N-terminal actin-binding and cysteine-rich domains (ABD1 + CRD) had a decreased risk of LGE and trended toward greater freedom from LGE. Patients with predicted present CTD (exactly the same as those with in-frame mutations) and ABD1 + CRD trended toward decreased risk of and greater freedom from depressed LVEF. In conclusion, genotypes previously implicated in altering the dystrophinopathic cardiac phenotype were not significantly related to LGE and depressed LVEF. Patients with predicted present CRD, CTD/in-frame mutations, and ABD1 + CRD trended toward milder cardiac phenotypes, suggesting that the reading-frame rule may be applicable to the cardiac phenotype. Genotype–phenotype correlations may help predict the cardiac phenotype for dystrophinopathic patients and guide future therapies.

To assess outcomes among patients with Duchenne muscular dystrophy receiving deflazacort or prednisone in real-world practice. Clinical data for 435 boys with Duchenne muscular dystrophy from Cincinnati Children’s Hospital Medical Center were studied retrospectively using time-to-event and regression analyses. Median ages at loss of ambulation were 15.6 and 13.5 years among deflazacort- and prednisone-initiated patients, respectively. Deflazacort was also associated with a lower risk of scoliosis and better ambulatory function, greater % lean body mass, shorter stature and lower weight, after adjusting for age and steroid duration. No differences were observed in whole body bone mineral density or left ventricular ejection fraction. This single center study adds to the real-world evidence associating deflazacort with improved clinical outcomes. This retrospective study described outcomes for boys with Duchenne muscular dystrophy treated at Cincinnati Children’s Hospital Medical Center with the glucocorticoids deflazacort (∼95% daily dosing) or prednisone (∼68% daily dosing). Patients receiving deflazacort had lower risk of losing ambulation, lost ambulation at older ages than those receiving prednisone, and had lower risk of scoliosis. Across clinic visits, deflazacort was associated with greater preservation of ambulatory and pulmonary function, shorter stature, lower bodyweight and greater % lean body mass. This study adds to the evidence associating real-world dosing of deflazacort with improved outcomes for patients with Duchenne muscular dystrophy.

Background Prior reports focus primarily on muscle fatty infiltration in Duchenne muscular dystrophy (DMD). However, the significance of muscle edema is uncertain. Objective To evaluate the frequency and degree of muscle fat and edema, and correlate these with clinical function. Materials and methods Forty-two boys (ages 5–19 years) with DMD underwent pelvic MRI. Axial T1- and fat-suppressed T2-weighted images were evaluated to grade muscle fatty infiltration (0–4) and edema (0–3), respectively. Degree and frequency of disease involvement were compared to clinical evaluations. Results Gluteus maximus had the greatest mean fatty infiltration score, followed by adductor magnus and gluteus medius muscles, and had the most frequent and greatest degree of fatty infiltration. Gluteus maximus also had the greatest mean edema score, followed by vastus lateralis and gluteus medius muscles. These muscles had the most frequent edema, although the greatest degree of edema was seen in other muscles. There was correlation between cumulative scores of fatty infiltration and all clinical evaluations ( P  < 0.05). Conclusion In DMD, the muscles with the most frequent fatty infiltration had the greatest degree of fatty infiltration and correlated with patient function. However, the muscles with the most frequent edema were different from those with the greatest degree of edema. Thus, edema may not predict patient functional status.

Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] ≥300–<400 or <400 m). Meta-analyses examined 6MWD change from baseline to week 48. Statistically significant differences in 6MWD change with ataluren versus placebo were observed across all three meta-analyses. Least-squares mean difference (95% CI): ITT (n = 342), +17.2 (0.2–34.1) m, p = 0.0473; ≥300–<400 m (n = 143), +43.9 (18.2–69.6) m, p = 0.0008; <400 m (n = 216), +27.7 (6.4–49.0) m, p = 0.0109. These meta-analyses support previous evidence for ataluren in slowing disease progression versus placebo in patients with nmDMD over 48 weeks. Treatment benefit was most evident in patients with a baseline 6MWD ≥300–<400 m (the ambulatory transition phase), thereby informing future trial design.

We describe two donor splice site mutations, affecting dystrophin exons 16 and 45 that led to Duchenne muscular dystrophy (DMD), through catastrophic inactivation of the mRNA. These gene lesions unexpectedly resulted in the retention of the downstream introns, thereby increasing the length of the dystrophin mRNA by 20.2 and 36 kb, respectively. Splice‐switching antisense oligomers targeted to exon 16 excised this in‐frame exon and the following intron from the patient dystrophin transcript very efficiently in vitro, thereby restoring the reading frame and allowing synthesis of near‐normal levels of a putatively functional dystrophin isoform. In contrast, targeting splice‐switching oligomers to exon 45 in patient cells promoted only modest levels of an out‐of‐frame dystrophin transcript after transfection at high oligomer concentrations, whereas dual targeting of exons 44 and 45 or 45 and 46 resulted in more efficient exon skipping, with concomitant removal of intron 45. The splice site mutations reported here appear highly amenable to antisense oligomer intervention. We suggest that other splice site mutations may need to be evaluated for oligomer interventions on a case‐by‐case basis. Two donor splice site mutations in dystrophin exons 16 and 45 led to DMD, through retention of the downstream introns, thereby increasing the length of the dystrophin mRNA by 20.2 kb and 36 kb, respectively. Antisense oligomer‐mediated exon skipping was used to remove the exons carrying the causative mutations to reframe the transcript and allow expression of a functional gene product.

Pediatricians should be familiar with the common presenting signs and symptoms of MD so that they can make a clinical diagnosis of possible MD based on the patient's medical history, a physical examination, and a CK screen. Appropriate referral to a neuromuscular specialist will then enable the precise diagnosis of MD to be made with definitive histologic, biochemical, and genetic testing.