Duchenne Natural History Study Research Articles

The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy.

Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (-0.80%) and SF (-0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (-11.01 mL/m2, p = 0.03) while for dp116 were correlated with decreased EF (-4.14%, p = <0.001). The rs10880 genotype in the LTBP4 gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, p = 0.002, and -10.62 mL/m2, p = 0.008) with a recessive model. We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD.

Efficacy and Safety of Viltolarsen in Boys With Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study.

Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations, resulting in absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, significantly increased dystrophin levels in patients with DMD. Presented here are completed study results of > 4 years of functional outcomes in viltolarsen-treated patients compared to a historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study [CINRG DNHS]). To evaluate the efficacy and safety of viltolarsen for an additional 192 weeks in boys with DMD. This phase 2, open-label, 192-week long-term extension (LTE) study (NCT03167255) evaluated the efficacy and safety of viltolarsen in participants aged 4 to < 10 years at baseline with DMD amenable to exon 53 skipping. All 16 participants from the initial 24-week study enrolled into this LTE. Timed function tests were compared to the CINRG DNHS group. All participants received glucocorticoid treatment. The primary efficacy outcome was time to stand from supine (TTSTAND). Secondary efficacy outcomes included additional timed function tests. Safety was continuously assessed. For the primary efficacy outcome (TTSTAND), viltolarsen-treated patients showed stabilization of motor function over the first two years and significant slowing of disease progression over the following two years compared with the CINRG DNHS control group which declined. Viltolarsen was well tolerated, with most reported treatment-emergent adverse events being mild or moderate. No participants discontinued drug during the study. Based on the results of this 4-year LTE, viltolarsen can be an important treatment strategy for DMD patients amenable to exon 53 skipping.

Modeling Early Heterogeneous Rates of Progression in Boys with Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) exhibits substantial variability in rates of disease progression and response to treatment. This has hindered treatment development and complicated interpretation of drug effects in clinical trials. We hypothesized that a multivariate combination of early-age clinical outcome measurements can explain differential disease progression. Data on boys with DMD (ages 4-<10 years), both treated with steroidal anti-inflammatories and untreated, were obtained from CINRG Duchenne Natural History Study (n = 209) and vamorolone VBP15-002/003/LTE (n = 46) studies. Velocities from three timed function tests (TFTs; stand from supine, run/walk 10 meters, and climb 4 stairs) were simultaneously modeled in a longitudinal latent class analysis. Three classes of differentially progressing early age DMD motor trajectories were identified. Quicker decline/progression was associated with lower baseline TFT velocities, earlier loss of ability to finish a TFT, and lower predicted velocities. Earlier substantial steroid exposure was associated with greater TFT velocities while the moderate progression class was observed to have the largest difference in performance between boys treated early with steroids vs. not. Sample size calculations with the class showing the largest treatment response showed a large reduction in required sample size as compared to using summaries from all participants. Gene mutations were also investigated in post-hoc analyses, with mutations near the beginning of the DMD gene (Dp427 absent and Dp140/Dp71 present) found to be enriched in the slowest progressing class. This study provides insight into the variation in DMD progression through a latent class analysis. Our findings show class-related trajectories of motor outcomes and pharmacological response to corticosteroids, and suggest that enrichment strategies and/or subgroup analyses could be considered further in design of therapeutic interventions in DMD.

Safety and effectiveness of ataluren in patients with nonsense mutation DMD in the STRIDE Registry compared with the CINRG Duchenne Natural History Study (2015–2022): 2022 interim analysis

ObjectiveStrategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, international, multicenter registry of real-world ataluren use in individuals with nonsense mutation Duchenne muscular dystrophy (nmDMD) in clinical practice. This updated interim report (data cut-off: January 31, 2022), describes STRIDE patient characteristics and ataluren safety data, as well as the effectiveness of ataluren plus standard of care (SoC) in STRIDE versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS).MethodsPatients are followed up from enrollment for at least 5 years or until study withdrawal. Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established predictors of disease progression.ResultsAs of January 31, 2022, 307 patients were enrolled from 14 countries. Mean (standard deviation [SD]) ages at first symptoms and at genetic diagnosis were 2.9 (1.7) years and 4.5 (3.7) years, respectively. Mean (SD) duration of ataluren exposure was 1671 (56.8) days. Ataluren had a favorable safety profile; most treatment-emergent adverse events were mild or moderate and unrelated to ataluren. Kaplan–Meier analyses demonstrated that ataluren plus SoC significantly delayed age at loss of ambulation by 4 years (p < 0.0001) and age at decline to %-predicted forced vital capacity of < 60% and < 50% by 1.8 years (p = 0.0021) and 2.3 years (p = 0.0207), respectively, compared with SoC alone.ConclusionLong-term, real-world treatment with ataluren plus SoC delays several disease progression milestones in individuals with nmDMD. NCT02369731; registration date: February 24, 2015.

Major Adverse Dystrophinopathy Events (MADE) score as marker of cumulative morbidity and risk for mortality in boys with Duchenne muscular dystrophy

BackgroundOverlapping symptoms from cardiomyopathy, respiratory insufficiency, and skeletal myopathy confound assessment of heart failure in Duchenne Muscular Dystrophy. We developed an ordinal scale of multiorgan clinical variables that reflect cumulative disease burden—the Major Adverse Dystrophinopathy Event (MADE) Score. We hypothesized that a higher MADE Score would be associated with increased mortality in boys with Duchenne Muscular Dystrophy. The Cooperative International Neuromuscular Research Group Duchenne Natural History Study dataset was utilized for validation. MethodsDuchenne Natural History Study variables were selected based on clinical relevance to prespecified domains: Cardiac, Pulmonary, Myopathy, and Nutrition. Severity points (0–4) were assigned and summed for study visits. MADE Score for cohorts defined by age, ambulatory status, and survival was compared at enrollment and longitudinally.Associations between MADE Score and mortality were examined. ResultsDuchenne Natural History Study enrolled 440 males, 12.6 ± 6.1 years old, with 3559 visits over 4.6 ± 2.8 years, 45 deaths. MADE Score increased with age and nonambulatory status. Mean MADE Score per visit was 19 ± 10 for those who died vs. 9.8 ± 9.3 in survivors p = 0.03. Baseline MADE Score >12 predicted mortality independent of age (78 % sensitivity, CPE.70). Rising MADE Score trajectory was associated with mortality in models adjusted for enrollment age, follow-up time, and ambulatory status, all p < 0.001. ConclusionA multiorgan severity score, MADE, was developed to track cumulative morbidities that impact heart failure in Duchenne muscular dystrophy. MADE Score predicted Duchenne Natural History Study mortality. MADE Score can be used for serial heart failure assessment in males with Duchenne muscular dystrophy and may serve as an endpoint for related clinical research.

P.22 Age at loss of ambulation in patients with DMD from the STRIDE registry and the CINRG natural history study: A matched cohort analysis

We examined if nonsense mutation Duchenne muscular dystrophy (nmDMD) patients receiving ataluren plus standard of care (SoC) in the strategic targeting of registries and international database of excellence (STRIDE) registry (NCT02369731) experienced a delay in age at loss of ambulation (LOA) versus DMD patients receiving SoC alone in the cooperative international neuromuscular research group (CINRG) Duchenne natural history study (NCT00468832). STRIDE is an ongoing, multicenter, observational registry providing data on ataluren use in nmDMD patients in routine clinical practice. Data were extracted on January 31, 2022. Propensity score matching identified STRIDE and CINRG patient cohorts (N=260) comparable in established predictors of disease progression: age at first symptoms; age at initiation of corticosteroid use; duration of deflazacort use; and duration of other corticosteroid use. Patients from CINRG who had received investigational drugs for DMD were excluded. Kaplan–Meier analyses were used to estimate age at LOA. The mean (standard deviation) ages at first symptoms in the STRIDE and CINRG cohorts (N=260 per cohort) were 2.8 (1.7) and 2.8 (1.5) years, respectively. Most patients (STRIDE vs CINRG) received corticosteroids for ≥12 months (85.0% vs 83.8%), with a similar proportion receiving deflazacort (47.7% vs 44.2%) or other corticosteroids (41.9% vs 43.5%). In the STRIDE cohort, 26.5% (69/260) of patients lost ambulation compared with 54.6% (142/260) of patients in the CINRG cohort. The median (95% confidence interval) ages at LOA (STRIDE vs CINRG) were 17.9 (14.8, not estimable) and 12.5 (12.0, 13.5) years, respectively. Kaplan–Meier analyses showed that ataluren plus SoC delayed age at LOA compared with SoC alone (p<0.0001). These Kaplan–Meier analyses showed that in routine clinical practice ataluren plus SoC delayed age at LOA by 5.4 years compared with SoC alone in patients with nmDMD.

P.68 Validation of a composite prognostic score for time to loss of ambulation in Duchenne muscular dystrophy

Loss of ambulation (LoA) is a critical milestone in the progression of Duchenne muscular dystrophy (DMD) that usually occurs by the early teens, with significant variation across individuals. Accurate individualized predictions of time to LoA are valuable for DMD drug development (e.g., enrichment of trial populations and benchmarking of long-term treatment outcomes), as well as for counseling of patients and caregivers (e.g., advance ordering of a power wheelchair, preparing home modifications for accessibility). A composite prognostic score for LoA was previously developed based data from 608 boys and 1,240 years of follow-up across multiple DMD natural history and placebo-arm data sources. Timed function tests, steroid type, height and weight were identified as the most important predictors of LoA. We independently validated this score using data from 226 patients with 819 years of follow-up in the CINRG Duchenne natural history study, which was not used for score development. The previously-defined prognostic groups showed excellent risk stratification in the validation data, with median times to LoA of 1.8, 3.8, 7.8 and >9.0 years across groups, compared with medians of 1.1, 2.1, 4.1 and >9.0 years in the training data. Risk groups were well-differentiated despite the use of different LoA definitions in the training data (inability to walk 10 meters or complete the 6-minute walk test) and validation data (full-time wheelchair dependence), but shifted to later median ages in the validation data. Simplified prognostic scores were also explored using classification and regression trees to identify functional thresholds that best predicted time to LoA. Individualized prediction of time to LoA is possible in DMD, and is most accurate when based on a composite profile of motor function. Calibration of prognostic scores to specific definitions of LoA is important for quantitative accuracy, and for applications in clinical management and drug development.

Delays in pulmonary decline in eteplirsen-treated patients with Duchenne muscular dystrophy.

Pulmonary decline is a major issue in patients with Duchenne muscular dystrophy (DMD). Eteplirsen is a United States-approved treatment for patients with DMD and exon 51 skip-amenable mutations. Previous analyses have shown that eteplirsen is associated with a statistically significant attenuation of pulmonary decline. In this study we evaluate the effect of eteplirsen treatment from newly available data sources on pulmonary function over time in patients with DMD. We used a post hoc pooled analysis to compare the percentage of predicted forced vital capacity (FVC%p) and projected time with pulmonary function milestones in patients with DMD and exon 51 skip-amenable mutations receiving eteplirsen (Studies 204 and 301) or standard of care (SoC; Cooperative International Neuromuscular Research Group Duchenne Natural History Study). A mixed model for repeated-measures framework was applied to evaluate the impact of eteplirsen. An average annual rate of FVC%p decline for eteplirsen-treated patients was estimated to be 3.47%, a statistically significant attenuation from the 5.95% rate of decline estimated in SoC patients (P=.0001). Using linear extrapolations of the model-estimated decline in FVC%p, the attenuation in FVC%p decline for eteplirsen-treated patients corresponded to a delay of 5.72 years in time to needing continuous ventilation, 3.31 years in time to needing nighttime ventilation, and 2.11 years in time to needing a cough assist device compared with SoC patients. The attenuation of FVC%p decline suggests that eteplirsen-treated patients had statistically significant and clinically meaningful attenuations in pulmonary decline compared with SoC patients.

Genetic modifiers of upper limb function in Duchenne muscular dystrophy

Genetic modifiers of Duchenne muscular dystrophy (DMD) are variants located in genes different from the disease-causing gene DMD, but associated with differences in disease onset, progression, or response to treatment. Modifiers described so far have been tested mainly for associations with ambulatory function, while their effect on upper limb function, which is especially relevant for quality of life and independence in non-ambulatory patients, is unknown. We tested genotypes at several known modifier loci (SPP1, LTBP4, CD40, ACTN3) for association with Performance Upper Limb version 1.2 score in an Italian multicenter cohort, and with Brooke scale score in the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS), using generalized estimating equation (GEE) models of longitudinally collected data, with age and glucocorticoid treatment as covariates. CD40 rs1883832, previously linked to earlier loss of ambulation, emerged as a modifier of upper limb function, negatively affecting shoulder and distal domains of PUL (p = 0.023 and 0.018, respectively) in the Italian cohort, as well as of Brooke score (p = 0.018) in the CINRG-DNHS. These findings will be useful for the design and interpretation of clinical trials in DMD, especially for non-ambulatory populations.

Major Adverse Dystrophinopathy Event Score as Marker of Cumulative Morbidity and Risk for Mortality in Boys with Duchenne Muscular Dystrophy

<h3>Purpose</h3> Accurate assessments of heart failure (HF) severity in Duchenne Muscular Dystrophy (DMD) is challenging due to overlapping symptoms from cardiomyopathy, respiratory insufficiency, and skeletal myopathy. We developed an ordinal scale of multiorgan clinical variables and events graded for severity that reflect cumulative disease burden-the <b>M</b>ajor <b>A</b>dverse <b>D</b>ystrophinopathy <b>E</b>vent <b>(MADE</b>) score. We hypothesized that a higher MADE score would be associated with increased mortality in DMD. We used the CINRG Duchenne Natural History Study (DNHS) dataset for MADE score validation. <h3>Methods</h3> DNHS variables were selected based on clinical relevance to prespecified MADE domains: Cardiac, Pulmonary, Myopathy, Nutrition. Severity points (0-4) were assigned and summed for study visits. MADE score for cohorts defined by age, ambulatory status, and survival were compared at enrollment and serially. Ability of baseline MADE score to predict mortality that occurred during the DNHS was examined. <h3>Results</h3> DNHS enrolled 440 males, 12.6 ± 6.1 years old, followed for 3,559 study visits over 4.6 ± 2.8 years, with 45 deaths. MADE score increased with age and was higher in the nonambulatory cohort. Effect of Cardiac and Pulmonary domains on total Score over time doubled and tripled respectively for nonambulatory vs ambulatory cohorts (p<.001). Mean MADE score per visit was 19 ± 10 for those who died vs. 9.8 ± 9.3 in survivors p=0.03. A baseline MADE score >12 predicted mortality independent of age (78% sensitivity, CPE.70). A rising MADE score trajectory was associated with mortality in models adjusted for enrollment age, follow-up time, and ambulatory status, all p<.001<b>.</b> Figure <h3>Conclusion</h3> A multiorgan severity score, MADE, was developed to track cumulative morbidities that impact HF in DMD. MADE score, independent of age, predicted DNHS mortality. MADE score can be used for serial HF assessment in nonambulatory DMD males and be optimized to serve as an endpoint for DMD clinical research.

Influence Of β1 Adrenergic Receptor Genotype On Longitudinal Measures Of Left Ventricular Ejection Fraction And Responsiveness To ß-blocker Therapy In Patients With Duchenne Muscular Dystrophy

<h3>Rationale</h3> Cardiovascular disease (CVD) is fast emerging as a significant source of morbidity and mortality in patients with Duchenne Muscular Dystrophy (DMD). Left ventricular dysfunction is a strong indicator of worsening prognosis in DMD patients. As such, left ventricular ejection fraction (LVEF) has been used to monitor cardiac health and guide therapy in this population. Evidence suggests that β₁-adrenoceptors (ADRB1) play a role in regulating cardiac function, whereby <i>more</i> functional ADRB1 genotype variants (e.g., Arg389) are associated with systemic hypertension, potentially contributing to poorer cardiac function and increased mortality risk in DMD patients with CVD. Additionally, patients expressing the Arg389 variant are more likely to be responders to ß-blocker therapy. Thus, the purpose of this study was to determine whether the longitudinal progression of decline in LVEF in DMD patients is moderated by ADRB1 genotype and whether the efficacy of ß-blocker therapy is influenced by genotype status. <h3>Methods</h3> Data from the CINRG Duchenne Natural History Study including 147 DMD patients (6-34 yrs) were analyzed with a focus on ADRB1 genotype variants. Patients were grouped by ADRB1 genotype resulting in Gly389 patients (homozygous for Gly at amino acid 389; <i>n</i> = 80), and Arg389 patients (homozygous or heterozygous for Arg at amino acid 16; <i>n</i> = 67). A generalized additive mixed effects model was used to examine differences in the nonlinear trend of LVEF across patient ages between genotype groups and for ß-blocker use after controlling for demographics, corticosteroid-use, ambulatory status, and clinic site. <h3>Results</h3> Both genotype groups displayed a progressive decline in LVEF starting around the mean age of ambulation loss (∼12 yrs). However, there was no difference between genotype groups in the progression of decline in LVEF. There was a significant effect of ß-blocker use on longitudinal LVEF, wherein patients on ß-blockers had systematically lower LVEF when compared to patients not on ß-blockers. However, the effect of ß-blocker therapy on LVEF was not affected by ADRB1 genotype. <h3>Conclusion</h3> There was no influence of ADRB1 genotype on longitudinal LVEF in our cohort. There was, however, a negative influence of ß-blocker use on LVEF. These data suggest that DMD patients do not demonstrate a genotypic "responder" effect to ß-blockers, and that ß-blocker therapy may be detrimental to cardiovascular health in patients with DMD.

Efficacy and Safety of Vamorolone in Duchenne Muscular Dystrophy

Vamorolone is a synthetic steroidal drug with potent anti-inflammatory properties. Initial open-label, multiple ascending dose-finding studies of vamorolone among boys with Duchenne muscular dystrophy (DMD) found significant motor function improvement after 6 months treatment in higher-dose (ie, ≥2.0 mg/kg/d) groups. To investigate outcomes after 30 months of open-label vamorolone treatment. This nonrandomized controlled trial was conducted by the Cooperative International Neuromuscular Research Group at 11 US and non-US study sites. Participants were 46 boys ages 4.5 to 7.5 years with DMD who completed the 6-month dose-finding study. Data were analyzed from July 2020 through November 2021. Participants were enrolled in a 24-month, long-term extension (LTE) study with vamorolone dose escalated to 2.0 or 6.0 mg/kg/d. Change in time-to-stand (TTSTAND) velocity from dose-finding baseline to end of LTE study was the primary outcome. Efficacy assessments included timed function tests, 6-minute walk test, and NorthStar Ambulatory Assessment (NSAA). Participants with DMD treated with glucocorticoids from the Duchenne Natural History Study (DNHS) and NorthStar United Kingdom (NSUK) Network were matched and compared with participants in the LTE study receiving higher doses of vamorolone. Among 46 boys with DMD who completed the dose-finding study, 41 boys (mean [SD] age, 5.33 [0.96] years) completed the LTE study. Among 21 participants treated with higher-dose (ie, ≥2.0 mg/kg/d) vamorolone consistently throughout the 6-month dose-finding and 24-month LTE studies with data available at 30 months, there was a decrease in mean (SD) TTSTAND velocity from baseline to 30 months (0.206 [0.070] rises/s vs 0.189 (0.124) rises/s), which was not a statistically significant change (-0.011 rises/s; CI, -0.068 to 0.046 rises/s). There were no statistically significant differences between participants receiving higher-dose vamorolone and matched participants in the historical control groups receiving glucocorticoid treatment (75 patients in DNHS and 110 patients in NSUK) over a 2-year period in NSAA total score change (0.22 units vs NSUK; 95% CI, -4.48 to 4.04]; P = .92), body mass index z score change (0.002 vs DNHS SD/mo; 95% CI, -0.006 to 0.010; P = .58), or timed function test change. Vamorolone at doses up to 6.0 mg/kg/d was well tolerated, with 5 of 46 participants discontinuing prematurely and for reasons not associated with study drug. Participants in the DNHS treated with glucocorticoids had significant growth delay in comparison with participants treated with vamorolone who had stable height percentiles (0.37 percentile/mo; 95% CI, 0.23 to 0.52 percentile/mo) over time. This study found that vamorolone treatment was not associated with a change in TTSTAND velocity from baseline to 30 months among boys with DMD aged 4 to 7 years at enrollment. Vamorolone was associated with maintenance of muscle strength and function up to 30 months, similar to standard of care glucocorticoid therapy, and improved height velocity compared with growth deceleration associated with glucocorticoid treatment, suggesting that vamorolone may be an attractive candidate for treatment of DMD. ClinicalTrials.gov Identifier: NCT03038399.

Knee Strength and Ankle Range of Motion Impacts on Timed Function Tests in Duchenne Muscular Dystrophy: In the Era of Glucocorticoids.

Duchenne Muscular Dystrophy (DMD) is a neuromuscular disorder that presents in childhood and is characterized by slowly progressive proximal weakness and lower extremity contractures that limit ambulatory ability [1, 2]. Contractures develop in the ankles, knees, and hips due to muscle imbalances, fibrotic changes, loss of strength, and static positioning [2, 5]. Currently, standards of care guidelines emphasize the importance of maintaining good musculoskeletal alignment through stretching, bracing, and glucocorticoid (GC) therapy to preserve strength and function. This is a retrospective analysis of prospectively collected data through the CINRG Duchenne Natural history study (DNHS). The objectives of this analysis are to understand the progression of ankle contractures for individuals with DMD and to investigate the relationship between progressive lower limb contractures, knee strength, and Timed Function Tests.A collection of TFTs including supine to stand (STS), 10 meter walk test (10MWT), and timed stair climbing (4SC) have been used to monitor disease progression and are predictive of loss of ambulation in these patients [4]. Multiple factors contribute to loss of ambulation, including progressive loss of strength and contracture development that leads to changing biomechanical demands for ambulation. A better understanding of the changes in strength and range of motion (ROM) that contribute to loss of function is important in a more individualized rehabilitation management plan. In this longitudinal study, we measured strength using quantitative muscle testing (QMT) with the CINRG Quantitative Measurement System (CQMS)), ROM was measuresed with a goniometer and TFTs were measured using a standard stopwatch and methodology. We enrolled 440 participants; mean baseline age was 8.9 (2.1, 28.0) years with 1321 observations used for analysis. GC use was stratified based on duration on drug with 18.7%at < 6 months or naïve; 4.3%<1 year; 58.0%1 < 10 years; and 19.3%between 10-25 years of GC use. Ankle ROM was better for those on GC compared to GC naive but did not significantly influence long-term progression rates. QMT, ROM, age and GCs contribute to speed of TFTs. Knee extension (KE) strength and Dorsiflexion (DF) ROM are significant predictors of speed for all TFTs (p < 0.001). Of the variables used in this analysis, KE strength is the primary predictor of walking speed, estimating that every pound increase in KE results in a 0.042 m/s improvement in 10MWT, and a smaller similar increase of 0.009 m/s with every degree of ankle DF ROM. GC use provides an improvement in strength and ROM but does not affect rate of change. Knee strength has a greater influence on speed of TFTs than DF ROM, although both are statistically significant predictors of speed. Results show that retaining knee strength [1, 2], along with joint flexibility, may be important factors in the ability to perform walking, climbing and supine to stand activities.

Influence of β2 adrenergic receptor genotype on longitudinal measures of forced vital capacity in patients with Duchenne muscular dystrophy

The progression of decline in forced vital capacity as percent predicated (FVC%p) is a strong indicator of worsening prognosis in patients with Duchenne muscular dystrophy (DMD). Evidence suggests that ß2 adrenergic (ADRB2) receptors may play a role in determining respiratory function, whereby more functional ADRB2 genotype variants (e.g., Gly16) are associated with improved pulmonary function. The purpose of this study was to determine the influence of ADRB2 genotype on longitudinal measures of FVC%p as a function of age in DMD patients. Data from the CINRG Duchenne Natural History Study including 169 DMD patients (5–25 yrs) were analyzed. A generalized additive mixed effects model was used to examine differences in the nonlinear trend of FVC%p across patient ages between genotype groups after controlling for patient demographics, corticosteroid-use, and ambulatory status. Both genotype groups displayed a progressive, maturational decline in FVC%p. Notwithstanding this decline, patients expressing the Gly16 polymorphism demonstrated systematically lower FVC%p values at any given age compared with patients expressing the Arg16 polymorphism (P < 0.01). Therefore, expressing the Gly16 polymorphism may prove detrimental to respiratory function in DMD patients. These data suggest maybe ADRB2 genotyping should be considered in the clinical management of DMD patients.

Rasch Analysis of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales Administered to Patients With Duchenne Muscular Dystrophy

ObjectivesThe objective of this study was to examine the psychometric properties of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0 GCS) in Duchenne muscular dystrophy (DMD), a rare, severely debilitating, and ultimately fatal neuromuscular disease. MethodsPatients with DMD were recruited from 20 centers across 9 countries as part of the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (NCT00468832). The psychometric properties of the PedsQL 4.0 GCS were examined using Rasch analysis. ResultsIn total, 329 patients with DMD (mean age 9 years, range 3–18 years, 75% ambulatory) completed the PedsQL 4.0 GCS. The most difficult instrument items, expressing the greatest loss in health-related quality of life, were those associated with emotional well-being (eg, being teased by other children, feeling sad, and not making friends), as opposed to somatic disability (eg, lifting heavy objects, participating in sports, and running). The mean item and person fit residuals were estimated at 0.301 (SD: 1.385) and −0.255 (1.504), respectively. In total, 87% (20 of 23) of items displayed disordered thresholds, and many exhibited nontrivial dependency. The overall item-trait interaction χ2 value was 178 (115 degrees of freedom, P<.001). Our analysis also revealed significant issues with differential item functioning, and by investigating residual principal component loadings, the PedsQL 4.0 GCS total score was found to be multidimensional. ConclusionsThe PedsQL 4.0 GCS records information clinically relevant to patients with DMD, but the total scale score may not be fit for purpose as a measure health-related quality of life in this disease population.

Longitudinal motor function in proximal versus distal DMD pathogenic variants.

There is considerable heterogenicity in clinical outcomes in Duchenne muscular dystrophy (DMD). The aim of this study was to assess whether dystrophin gene (DMD) pathogenic variant location influences upper or lower extremity motor function outcomes in a large prospective cohort. We used longitudinal timed and quantitative motor function measurements obtained from 154 boys with DMD over a 10-y period by the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS) to understand how the trajectories of motor function differ based on proximal versus distal DMD pathogenic variants. Proximal variants were defined as located proximal to 5' DMD intron 44, and distal variants as those including nucleotides 3' DMD including intron 44. Distal DMD variants are predicted to alter the expression of short dystrophin isoforms (Dp140, Dp116, and Dp71). We compared various upper extremity and lower extremity motor function measures in these two groups, after adjusting for total lifetime corticosteroid use. The time to loss-of-ambulation and timed motor function measurements of both upper and lower limbs over a 10-y period were comparable between boys with proximal (n=53) and distal (n=101) DMD pathogenic variants. Age had a significant effect on several motor function outcomes. Boys younger than 7y of age (n=49) showed gain in function whereas boys 7y and older (n=71) declined, regardless of dystrophin pathogenic variant location. The longitudinal decline in upper and lower motor function is independent of proximal versus distal location of DMD pathogenic variants.

Treatment with Ataluren for Duchene Muscular Dystrophy.

Investigators from Europe and the USA, representing the STRIDE Registry and Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS), examined the effectiveness of ataluren and standard of care in the Registry versus stand of care alone in the CINRG DNHS.

Comparison of Serum Pharmacodynamic Biomarkers in Prednisone-Versus Deflazacort-Treated Duchenne Muscular Dystrophy Boys.

Prednisone (Pred) and Deflazacort (Dfz) are commonly used glucocorticoids (GCs) for Duchenne muscular dystrophy (DMD) treatment and management. While GCs are known to delay the loss of ambulation and motor abilities, chronic use can result in onerous side effects, e.g., weight gain, growth stunting, loss of bone density, etc. Here, we use the CINRG Duchenne natural history study to gain insight into comparative safety of Pred versus Dfz treatment through GC-responsive pharmacodynamic (PD) biomarkers. Longitudinal trajectories of SOMAscan® protein data obtained on serum of DMD boys aged 4 to 10 (Pred: n = 7; Dfz: n = 8) were analyzed after accounting for age and time on treatment. Out of the pre-specified biomarkers, seventeen candidate proteins were differentially altered between the two drugs (p < 0.05). These include IGFBP-2 and AGER associated with diabetes complications, and MMP-3 associated with extracellular remodeling. As a follow-up, IGFBP-2, MMP-3, and IGF-I were quantified with an ELISA using a larger sample size of DMD biosamples (Dfz: n = 17, Pred: n = 12; up to 76 sera samples) over a longer treatment duration. MMP-3 and IGFBP-2 validated the SOMAscan® signal, however, IGF-I did not. This study identified GC-responsive biomarkers, some associated with safety, that highlight differential PD response between Dfz and Pred.

REGISTRIES, CARE, QUALITY OF LIFE, MANAGEMENT OF NMD: P.345 Rasch analysis of the pediatric quality of life inventory 4.0 generic core scales administered to patients with Duchenne muscular dystrophy

The Pediatric quality of life inventory 4.0 generic core scales (PedsQL 4.0 GCS) is one of the most commonly applied measures of health-related quality of life (HRQoL) in paediatric populations. The objective of this study was to examine the psychometric properties of the PedsQL 4.0 GCS administered to patients with Duchenne muscular dystrophy (DMD), a rare, X-linked, severely debilitating, and ultimately fatal neuromuscular disease characterised by progressive muscle weakness. Patients with DMD were recruited from 20 centres across nine countries as part of the Cooperative International Neuromuscular Research Group Duchenne natural history study (NCT00468832).

Genetic modifiers of respiratory function in Duchenne muscular dystrophy.

ObjectiveRespiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG‐DNHS).Methods and ResultsGeneralized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow‐up time of 4.5 years, estimated that forced vital capacity (FVC) declined yearly by −4.2%, forced expiratory volume in 1 sec by −5.0%, and peak expiratory flow (PEF) by −2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3’ of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately −6%) PFT values, a finding independently validated in the CINRG‐DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta‐analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF.InterpretationThese findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.