Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can ...confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10 m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that α-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that α-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients.
We performed an observational, natural history study of males with in‐frame dystrophin gene deletions causing Becker muscular dystrophy (BMD). A prospective natural history study collected ...longitudinal medical, strength, and timed function assessments. Eighty‐three participants with genetically confirmed BMD were enrolled (age range 5.6–75.4 years). Lower extremity function and the percentage of participants who retained ambulation declined across the age span. The largest single group of participants had in‐frame deletions that corresponded to an out‐of‐frame deletion treated with an exon 45 skip to restore the reading frame. This group of 54 participants showed similarities in baseline motor functional assessments when compared to the group of all others in the study. A prospective natural history cohort with in‐frame dystrophin gene deletions offers the potential to contribute to clinical trial readiness for BMD and to analyze therapeutic benefit of exon skipping for Duchenne muscular dystrophy.
Evidence on the long-term efficacy of steroids in Duchenne muscular dystrophy (DMD) after loss of ambulation is limited.
Characterize and compare disease progression by steroid treatment (prednisone, ...deflazacort, or no steroids) among non-ambulatory boys with DMD.
Disease progression was measured by functional status (Performance of Upper Limb Module for DMD 1.2 PUL and Egen Klassifikation Scale Version 2 EK scale) and by cardiac and pulmonary function (left ventricular ejection fraction LVEF, forced vital capacity FVC % -predicted, cough peak flow CPF). Longitudinal changes in outcomes, progression to key disease milestones, and dosing and body composition metrics were analyzed descriptively and in multivariate models.
This longitudinal cohort study included 86 non-ambulatory patients with DMD (mean age 13.4 years; n = 40 deflazacort, n = 29 prednisone, n = 17 no steroids). Deflazacort use resulted in slower average declines in FVC % -predicted vs. no steroids (+3.73 percentage points/year, p < 0.05). Both steroids were associated with significantly slower average declines in LVEF, improvement in CPF, and slower declines in total PUL score and EK total score vs. no steroids; deflazacort was associated with slower declines in total PUL score vs. prednisone (all p < 0.05). Both steroids also preserved functional abilities considered especially important to quality of life, including the abilities to perform hand-to-mouth function and to turn in bed at night unaided (all p < 0.05 vs. no steroids).
Steroid use after loss of ambulation in DMD was associated with delayed progression of important pulmonary, cardiac, and upper extremity functional deficits, suggesting some benefits of deflazacort over prednisone.
We studied the reliability of a series of endpoints in an evaluation of subjects with Duchenne muscular dystrophy (DMD). The endpoints included quantitative muscle tests (QMTs), timed function tests, ...forced vital capacity (FVC), and manual muscle tests (MMT). Thirty‐one ambulatory subjects with DMD (mean age 8.9 years; range 5–16 years) were evaluated at eight sites by 15 newly trained evaluators as a test of interrater reliability of outcome measures. Both total QMT score intraclass correlation coefficient (ICC) 0.96 and individual QMT assessments (ICC 0.85–0.96) were highly reliable. Forced vital capacity and all timed function tests were also highly reliable (ICC 0.97–0.99). MMT was the least reliable assessment method (ICC 0.61). These data suggest that primary surrogate outcome measures in large multicenter clinical trials in DMD should use QMT, FVC, or time function tests to obtain maximum power and greatest sensitivity. Muscle Nerve, 2006
The 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.
Patients 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.
In 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.
The 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.
•The Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0 GCS) is a commonly used measure of health-related quality of life in patients with Duchenne muscular dystrophy.•We evaluate the psychometric properties of the PedsQL 4.0 GCS using Rasch analysis.•We show that the PedsQL 4.0 GCS may not be a valid measure of health-related quality of life in Duchenne muscular dystrophy.
Duchenne muscular dystrophy (DMD) is the most common X-linked neuromuscular condition manifested by progressive skeletal muscle weakness, cardiopulmonary involvement and cognitive deficits. ...Neurodevelopmental symptoms and signs are under-appreciated in this population despite the recognition that cognition has a major impact on quality-of-life. We describe the neurodevelopmental needs in a large cohort of young boys with DMD from the DMD Natural History Study (DNHS). We explore the association between neurodevelopmental needs and DMD mutation location, and with glucocorticoid use. Methods: We prospectively evaluated 204 participants between ages 4 to less than 9 years of age with DMD as part of a large, longitudinal, international DNHS. We obtained parent- or primary care-giver report of neurodevelopmental needs as part of their study visit. We assessed the relationship between parent/care-giver neurodevelopmental needs and DMD mutation location, and glucocorticoid use.
The neurodevelopmental needs that were most commonly reported included speech delay (33%), mild developmental delay (24%), significant behavioral problems (16.5%), language impairment (14.5%), learning disability (14.5%), attention-deficit hyperactivity disorder (5%) and autism spectrum disorder (3%). Neurodevelopmental needs were more commonly reported by care-givers in those with DMD mutations downstream of exon 51. There was no relationship between care-giver reported neurodevelopmental needs and glucocorticoid use.
Neurodevelopmental needs are highly prevalent in young boys with DMD. Care-givers report higher neurodevelopmental needs when subjects have DMD mutations downstream of exon 51. Early interventions aimed at cognitive health are critical to improve the quality-of-life of individuals with DMD.
ClinicalTrials.gov NCT00468832.
ABSTRACT
Introduction: Glucocorticoid (GC) therapy in Duchenne muscular dystrophy (DMD) has altered disease progression, necessitating contemporary natural history studies. Methods: The Cooperative ...Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD‐NHS) enrolled 340 DMD males, ages 2–28 years. A comprehensive battery of measures was obtained. Results: A novel composite functional “milestone” scale scale showed clinically meaningful mobility and upper limb abilities were significantly preserved in GC‐treated adolescents/young adults. Manual muscle test (MMT)‐based calculations of global strength showed that those patients <10 years of age treated with steroids declined by 0.4±0.39 MMT unit/year, compared with −0.4±0.39 MMT unit/year in historical steroid‐naive subjects. Pulmonary function tests (PFTs) were relatively preserved in steroid‐treated adolescents. The linearity and magnitude of decline in measures were affected by maturational changes and functional status. Conclusions: In DMD, long‐term use of GCs showed reduced strength loss and preserved functional capabilities and PFTs compared with previous natural history studies performed prior to the widespread use of GC therapy. Muscle Nerve, 2013
The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) ...varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor β TGFβ-binding protein 4) have been established as DMD modifiers. We performed a genome-wide association study of age at LoA in a sub-cohort of European or European American ancestry (n = 109) from the Cooperative International Research Group Duchenne Natural History Study (CINRG-DNHS). We focused on protein-altering variants (Exome Chip) and included glucocorticoid treatment as a covariate. As expected, due to the small population size, no SNPs displayed an exome-wide significant p value (< 1.8 × 10−6). Subsequently, we prioritized 438 SNPs in the vicinities of 384 genes implicated in DMD-related pathways, i.e., the nuclear-factor-κB and TGFβ pathways. The minor allele at rs1883832, in the 5′-untranslated region of CD40, was associated with earlier LoA (p = 3.5 × 10−5). This allele diminishes the expression of CD40, a co-stimulatory molecule for T cell polarization. We validated this association in multiple independent DMD cohorts (United Dystrophinopathy Project, Bio-NMD, and Padova, total n = 660), establishing this locus as a DMD modifier. This finding points to cell-mediated immunity as a relevant pathogenetic mechanism and potential therapeutic target in DMD.
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