Cohort Of Duchenne Muscular Dystrophy Patients Research Articles

Left Atrial Phasic Function via Cardiac Magnetic Resonance Imaging in Patients with Duchenne Muscular Dystrophy.

Cardiac dysfunction is a leading cause of morbidity and mortality in Duchenne muscular dystrophy (DMD). Left atrial (LA) function is a poorly understood concept in this patient population, and research suggests underlying structural changes that could affect atrial function. Cardiac magnetic resonance (CMR) imaging may provide an important non-invasive approach to evaluating LA function. This study was a single center retrospective review of consecutive CMR studies over a 1year period comparing LA phasic function within a cohort of DMD patients, and to those with structurally and functionally normal hearts. LA strain measurements including global reservoir, conduit, boost-pump strain, and LA volumes were obtained retrospectively. Spearman correlation analyses were performed on atrial strain measurements. 107 DMD and 79 normal CMR studies were included. The DMD cohort had worse systolic function (p < 0.001), smaller indexed max LA and left ventricular (LV) volumes (p < 0.001), and greater LA emptying fraction (p < 0.001). In the DMD cohort, emptying fraction decreased with advanced patient age (p < 0.001) and diminishing systolic function (p < 0.001). DMD patients with moderate or severe LV dysfunction demonstrated lower LA emptying fraction (p = 0.002), more impaired 2-chamber LA reservoir (p = 0.003), and LA pump (p = 0.006) and conduit strain (p = 0.018). DMD patients with preserved function have lower indexed LA volumes with higher LA emptying fractions than controls. Progression of disease and age is associated with decreased LA emptying fraction with early manifestations in reservoir and conduit strain. These findings suggest that strain markers of LA compliance and early left ventricular relaxation are associated with worsening cardiomyopathy in the DMD population.

Bone health in Duchenne muscular dystrophy: clinical and biochemical correlates.

An increased fracture risk is commonly reported in Duchenne muscular dystrophy (DMD). Our aim was to investigate bone mineral density (BMD) and bone turnover, including sclerostin, and their association with markers of cardiac and respiratory performance in a cohort of DMD subjects. In this single center, cross sectional observational study, lumbar spine (LS) BMD Z-scores, C-terminal telopeptide of procollagen type I (CTX) and osteocalcin (BGP), as bone resorption and formation markers, respectively, and sclerostin were assessed. Left ventricular ejection fraction (LVEF) and forced vital capacity (FVC) were evaluated. Clinical prevalent fractures were also recorded. Thirty-one patients [median age = 14 (12-21.5) years] were studied. Ambulant subjects had higher LS BMD Z-scores compared with non-ambulant ones and subjects with prevalent clinical fractures [n = 9 (29%)] showed lower LS BMD Z-scores compared with subjects without fractures. LS BMD Z-scores were positively correlated with FVC (r = 0.50; p = 0.01), but not with glucocorticoid use, and FVC was positively associated with BGP (r = 0.55; p = 0.02). In non-ambulant subjects, LS BMD Z-scores were associated with BMI (r = 0.54; p = 0.02) and sclerostin was associated with age (r = 0.44; p = 0.05). Age, BMI, FVC and sclerostin were independently associated with LS BMD Z-score in a stepwise multiple regression analysis. Older age, lower BMI, FVC and sclerostin were associated with lower LS BMD Z-scores. In a cohort of DMD patients, our data confirm low LS BMD Z-scores, mainly in non-ambulant subjects and irrespective of the glucocorticoid use, and suggest that FVC and sclerostin are independently associated with LS BMD Z-scores.

Normalized grip strength is a sensitive outcome measure through all stages of Duchenne muscular dystrophy.

The main aim was to explore the changes in hand-grip strength in patients with Duchenne muscular dystrophy (DMD) aged 5-29years. Secondary aims were to test the effect of mutation, ambulatory status and glucocorticoid use on grip strength and its changes over time and to compute the number of subjects needed for a clinical trial to stabilize grip strength. The analysis was performed on data collected during five international natural history studies on a cohort of DMD patients. Two hundred and two patients with genetically proven DMD were pooled from five different natural history studies. Excepting 13 patients with only one visit, the mean duration of follow-up was 2.2 ± 1.6years. A total of 977 measurement points were collected. Grip strength was measured on the dominant side with a high precision dynamometer. The analysis was performed using absolute values and normalized values expressed in percentage of predicted values for age. For absolute values, grip strength typically increased in ambulatory boys and decreased in non-ambulatory patients. However, when normalized, grip strength was already reduced at age 5years and thereafter continued to fall away from normal values. The weaker the patients, the less strength they are prone to lose over again. Grip strength constitutes a sensitive and continuous outcome measure that can be used across all stages of DMD. Its measurement is easy to standardized, can be used in ambulatory and non-ambulatory patients and does not present any floor or ceiling effect. It is thus attractive as an outcome measure in therapeutic trials.

The Role of Prophylactic Heart Failure Therapy in Duchenne Muscular Dystrophy

Purpose There is variable practice and debate surrounding prophylactic heart failure (HF) therapy in Duchenne Muscular Dystrophy (DMD) patients with normal systolic function . We sought to determine the impact of HF medications including ACE inhibitors and ARB on the development of moderate systolic dysfunction or death in a cohort of DMD patients. Methods We performed a retrospective cohort study of DMD patients followed at 17 centers across North America from 1/1/2005-12/31/2015. Inclusion criteria were normal systolic function on baseline echocardiogram (ejection fraction (EF) ≥ 55%) and age ≥ 9 years during the study. Moderate systolic dysfunction was defined as an EF≤40% or shortening fraction ≤21% if EF was not available. We compared the composite outcome of moderate systolic dysfunction or death in patients who started HF therapies before evidence of systolic dysfunction (PPX) vs those who did not (non-PPX) using a Cox proportional hazards regression model adjusting for baseline age. We also compared prophylaxis with ACE/ARB (ACE/ARB PPX) to non-PPX. Results 277 males with DMD and normal systolic function were included. Prophylactic HF medications were used in 70 patients (25%) which included ACE/ARB (44, 63%), beta blocker (26, 37%), aldosterone blockade (6, 9%) and digoxin (5, 7%). Medications began at a mean (SD) age of 13.6 (4) years. Mean baseline ages were 10.7 (4.2) and 9.9 (3.9) years in the PPX and non-PPX groups (p=0.16), while mean age to develop moderate systolic dysfunction was 18.6 (5.4) and 16.8 (4.0) in the PPX and non-PPX groups (p=.005). The risk of developing moderate systolic dysfunction or death was 50% lower in the PPX group compared to the non-PPX group (HR=0.50; p=.044) and 79% lower in the ACE/ARB PPX group (N=38) compared to the non-PPX group (HR=0.21; p=0.035) (Figure 1). Conclusion There is variability in the use and choice of prophylactic HF medications in boys with DMD. This cohort showed a benefit to introduction of ACE/ARBs prior to evidence of systolic dysfunction.

Cardiopulmonary phenotypic discordance is common in Duchenne muscular dystrophy.

To determine the prevalence of discordant cardiopulmonary function among patients with Duchenne muscular dystrophy (DMD) in our clinic. Retrospective chart review from 1999 to 2017. DMD patients age ≥ 18 years, alive, with discordant cardiopulmonary function. No patients received glucocorticoid therapy. Discordant cardiopulmonary function was defined as either: good heart function (EF ≥ 40%) and bad lung function (FVC < 1 L) (Group A); or, bad heart function (EF < 40%) and good lung function (FVC ≥ 1 L) (Group B). Among 74 eligible patients, 25 patients (34%) had discordant cardiopulmonary function (21 patients in Group A and 4 patients in Group B). Three dystrophin mutations were shared by >2 patients (nine patients with deletion of exon 44; three patients with deletion of exon 51; three patients with duplication of exon 2). Among the 15 patients with a shared genotype, eight patients (53%) had discordant cardiopulmonary function (five patients in group A, three patients in group B). Twenty-six patients had a deletion involving or distal to exon 45. Ten of these patients (38%) had discordant cardiopulmonary function (eight patients in Group A, two patients in Group B). In our cohort of DMD patients, discordant cardiopulmonary function was common (present in one-third of our patients), and the dystrophin genotype did not reliably predict a patient's cardiopulmonary phenotype. If confirmed by larger, multi-center studies, our findings have significant implications for predicting patient prognosis, evaluating DMD therapies, and designing new DMD therapies.

S.P.56 Early neurodevelopmental findings in young children with Duchenne muscular dystrophy

Abstract Cognitive abilities have been extensively studied in children and adults with Duchenne muscular dystrophy (DMD) but less has been reported on younger children. This is not surprising as the diagnosis of DMD remains at a mean age of 4 and 6 months. The aim of this study was to assess neurodevelopmental abilities before the age of 4 years in a cohort of DMD patients in whom early diagnosis was possible because of incidental raised creatine kinase levels, family history or neonatal screenings. Sixty-six children with a diagnosis of DMD of age between 7 and 43 months (mean 27 months) were included in the study. All children were assessed using the Griffiths Mental Development Scales, establishing both total scores and subscores for each of the subscales. Thirty-six of the 66 children had a developmental quotient (DQ) > 85, 21 had a DQ between 70 and 84 and 9 below 70. The mean total DQ was 86 (SD 16.07) and the mean scores for each subscale were as follows: (A) locomotor: 79 (19.47), (B) personal social: 91 (18.48), (C) hearing and speech: 85 (23.59), (D) eye hand coordination: 87 (17.20), (E) performance: 88 (18.40), (F) practical reasoning: 95 (16.08). (Scale F only for patients older than 2 years.) Details of mutations were available in 58 of the 66 children included. Low DQ were found in five of the 26 (18.5 %) patients with mutations before exon 44, in 15 of the 29 with mutations between 44 and 55 (51.7 %) and in all three with mutations in the exons beyond exon 55. it Conclusions: The DQ found in our cohort was on average one SD below a DQ of 100 with approximately 45% of the children having a DQ below 85. The locomotor scale had the lowest scores but even when we excluded the locomotor scale, a DQ below 85 was found in 28 patients (43%).