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BACKGROUND AND PURPOSE: Treatment with glucocorticoids (GCs) is part of the standard of care in Duchenne muscular dystrophy, but excess weight gain and height stunting are common side-effects. It is still unclear how these growth-related side-effects affect motor function. METHODS: This retrospective cohort study utilized 2228 observations from 648 participants in the UK NorthStar database who had growth and ambulation data recorded between 2006 and 2020. Joint modelling was used to analyse the effect of longitudinal growth centiles on loss of ambulation with respect to GC type and regimen. RESULTS: Loss of ambulation was observed in 113 patients. National estimates of loss of ambulation age were updated by GC group and showed no significant association between loss of ambulation risk and absolute growth centile. However, yearly drift in weight and/or height centile had an associated risk effect on loss of ambulation. Over a 2-year period, a yearly drift in weight from the 50th to the 75th, 75th to the 90th and 90th to the 95th centile was associated with 138%, 118% and 64% increased risk of loss of ambulation, respectively. Conversely, a 2-year drift in height from the 50th to the 25th, 25th to the 10th and 10th to the 5th centile was associated with 53%, 49% and 35% decreased risk of loss of ambulation, respectively. CONCLUSIONS: Our results suggest a complex relationship between growth and loss of ambulation in Duchenne muscular dystrophy boys on chronic GCs, the first step in understanding the effects of drugs which also affect growth patterns.
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BACKGROUND: Duchenne muscular dystrophy (DMD) is a genetic disease resulting in progressive muscle weakness, loss of ambulation, and cardiorespiratory complications. Direct estimation of health-related quality of life for patients with DMD is challenging, highlighting the need for proxy measures. This study aims to catalog and compare existing published health state utility estimates for DMD and related conditions. METHODS: Using two search strategies, relevant utilities were extracted from the Tufts Cost-Effectiveness Analysis Registry, including health states, utility estimates, and study and patient characteristics. Analysis One identified health states with comparable utility estimates to a set of published US patient population utility estimates for DMD. A minimal clinically important difference of ± 0.03 was applied to each DMD utility estimate to establish a range, and the registry was searched to identify other health states with associated utilities that fell within each range. Analysis Two used pre-defined search terms to identify health states clinically similar to DMD. Mapping was based on the degree of clinical similarity. RESULTS: Analysis One identified 4,308 unique utilities across 2,322 cost-effectiveness publications. The health states captured a wide range of acute and chronic conditions; 34% of utility records were extrapolated for US populations (n = 1,451); 1% were related to pediatric populations (n = 61). Analysis Two identified 153 utilities with health states clinically similar to DMD. The median utility estimates varied among identified health states. Health states similar to the early non-ambulatory DMD phase exhibited the greatest difference between the median estimate of the sample (0.39) and the existing estimate from published literature (0.21). CONCLUSIONS: When available estimates are limited, using novel search strategies to identify utilities of clinically similar conditions could be an approach for overcoming the information gap. However, it requires careful evaluation of the utility instruments, tariffs, and raters (proxy or self).
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Distrofia Muscular de Duchenne , Calidad de Vida , Humanos , Estado de Salud , Masculino , Sistema de Registros , Análisis Costo-Beneficio , Niño , Años de Vida Ajustados por Calidad de VidaRESUMEN
Background: The prognosis of Duchenne muscular dystrophy (DMD) is poor once it develops to the stage of cardiac impairment. Recent studies have demonstrated that electrocardiogram (ECG), which consists of general ECG and vectorcardiogram (VCG), retains an extremely powerful role in the assessment of patients with reduced left ventricular (LV) systolic dysfunction. However, data regarding VCG recordings in DMD and its prognostic value for reduced left ventricular ejection fraction (LVEF) of DMD have never been reported. This study aims to describe the characteristics of VCG in children with DMD and to explore the predictive value of VCG for reduced LVEF in children with DMD. Methods: A total of 306 patients with a known diagnosis of DMD confirmed by the genetic test were retrospectively enrolled at our hospital between August 2018 and August 2022. This resulted in a total study group of 486 VCG recordings. Among them, 75 DMD patients who underwent cardiac magnetic resonance (CMR) later after one year follow-up were prospectively enrolled. The trend of VCG parameters of DMD patients across the different age span were compared with age-matched normal children. Concordance statistic analysis was further performed to assess the validity of VCG parameters in predicting the occurrence of reduced LVEF in patients with DMD. Results: DMD patients have a significantly higher heart rate, R waves in V1, QRS loop percentage in the right anterior quadrant in the horizontal plane (horizontal quadrant II) and QRS loop percentage in the anterior superior quadrant in the sagittal plane (sagittal quadrant IV) than normal children. Concordance statistic (C-statistic) showed an area under the curve of quadrant IV in the sagittal plane of baseline was 0.704. The receiver operating characteristic (ROC) curve shows that quadrant IV in the sagittal plane of 7.57% was the optimal cutoff with a sensitivity of 53.3% and a specificity of 88.3% for predicting reduced LVEF in DMD patients. Conclusions: Our study firstly showed that QRS loop percentage in the right anterior quadrant in the horizontal plane (horizontal quadrant II) and QRS loop percentage in the anterior superior quadrant in the sagittal plane (sagittal quadrant IV) could be abnormal in DMD boys as early as before 5 years old. Evaluation of the myocardium by VCG in the early age to predict possible cardiac systolic dysfunction may have important implications for the ongoing management of DMD boys.
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Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD), however, in the mdx mouse model of DMD, the cardiac phenotype differs from that seen in DMD-associated cardiomyopathy. Although some have used pharmacologic stress to stimulate injury and enhance cardiac pathology in the mdx model, many methods lead to high mortality with variable cardiac outcomes, and do not recapitulate the structural and functional cardiac changes seen in human disease. Here, we describe a simple and effective method to enhance the cardiac phenotype model in mdx mice using advanced 2D and 4D high-frequency ultrasound to monitor cardiac dysfunction progression in vivo. For our study, mdx and wild-type (WT) mice received daily low-dose (2 mg/kg/day) isoproterenol injections for 10 days. Histopathologic assessment showed that isoproterenol treatment increased myocyte injury, elevated serum cardiac troponin I levels, and enhanced fibrosis in mdx mice. Ultrasound revealed reduced ventricular function, decreased wall thickness, increased volumes, and diminished cardiac reserve in mdx mice compared to wild-type. Our findings highlight the utility of challenging mdx mice with low-dose isoproterenol as a valuable model for exploring therapies targeting DMD-associated cardiac pathologies.
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BACKGROUND: Due to progressive muscle wasting and weakness in patients with Duchenne Muscular Dystrophy (DMD), physical fatigability increases, upper extremity function reduces, which negatively impacts quality of life. Assistive technology such as dynamic arm supports (DAS) may help reduce this fatigability. This study aims to assess whether the novel Yumen 'EXone' DAS can reduce upper extremity fatigue and fatigability in DMD patients and healthy controls (HC), both with and without the DAS. Additionally, longitudinal changes in DMD patients were evaluated. METHODS: Five DMD patients from the Yumen Bionics pioneer program and five HCs participated. Two submaximal tests simulating drinking and reaching were performed for two minutes, each with and without DAS. DMD participants completed these tests twice, at baseline (T0) and after 6-9 months (T1), while HCs completed them once. Physical fatigability was measured by the number of repetitions and changes in surface electromyography (sEMG) amplitude. Subjective fatigue was assessed using the Borg Scale (6-20) Rate of Perceived Exertion (RPE). RESULTS: DMD participants generally performed more repetitions with the DAS than without. HCs showed similar or increased repetitions with the DAS. Assessing fatigability with sEMG was difficult due to the compensatory mechanisms used for the tests. Subjective fatigue scores on the Borg Scale were lower with the DAS for both DMD patients and HCs. CONCLUSION: The Yumen 'EXone' DAS effectively reduces both fatigue and fatigability in DMD patients and healthy controls. Despite the methodological shortcomings, this research is one of the first studies investigating the impact of DAS on fatigue and fatigability.
This study is one of the pioneering studies investigating the impact of a dynamic arm support on fatigue and fatigability in Duchenne Muscular Dystrophy.Both, physical fatigability and experienced fatigue, decrease when using a dynamic arm support.Using sEMG to assess fatigability in DMD is difficult due to the compensatory mechanisms used for daily life task performance.Reduced fatigue and fatigability when using a dynamic arm support could be a significant reason for its use, alongside enhanced arm functionality.
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BACKGROUND: Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disorder that leads to mobility loss and life-threatening cardiac or respiratory complications. Quantitative ultrasound (QUS) envelope statistics imaging, which characterizes fat infiltration and fibrosis in muscles, has been extensively used for DMD evaluations. PURPOSE: Notably, changes in muscle microstructures also result in acoustic attenuation, potentially serving as another crucial imaging biomarker for DMD. Expanding upon the reference frequency method (RFM), this study contributes to the field by introducing the robust RFM (RRFM) as a novel approach for ultrasound attenuation imaging in DMD. METHODS: The RRFM algorithm was developed using an iterative reweighted least squares technique. We conducted standard phantom measurements with a clinical ultrasound system equipped with a linear array transducer to assess the improvement in attenuation estimation bias by RRFM. Additionally, 161 DMD patients, included in both a validation dataset (n = 130) and a testing dataset (n = 31), underwent ultrasound scanning of the gastrocnemius for RRFM-based attenuation imaging. The diagnostic performances for ambulatory functions and discrimination between early and late ambulatory stages were evaluated and compared with those of QUS envelope statistics imaging (involving Nakagami distribution, homodyned K distribution, and entropy values) using the area under the receiver operating characteristic curve (AUROC). RESULTS: The results indicated that the RRFM method more closely matched the actual attenuation properties of the phantom, reducing measurement bias by 50% compared to conventional RFM. The AUROCs for RRFM-based attenuation imaging, used to discriminate between early and late ambulatory stages, were 0.88 and 0.92 for the validation and testing datasets, respectively. These performances significantly surpassed those of QUS envelope statistics imaging (p < 0.05). CONCLUSIONS: Ultrasound attenuation imaging employing RRFM may serve as a sensitive tool for evaluating the progression of ambulatory function deterioration, offering substantial potential for the health management and follow-up care of DMD patients.
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INTRODUCTION/AIMS: The dystrophinopathies primarily affect males; however, female carriers of pathogenic dystrophin variants can develop skeletal muscle symptoms. This study aimed to evaluate muscle involvement and symptoms in females with dystrophinopathy using quantitative magnetic resonance imaging (MRI), functional assessments, and patient-reported outcomes. METHODS: Controls and females with dystrophinopathy with muscle symptoms of pain, weakness, fatigue, or excessive tightness were enrolled in this cross-sectional study. Participants underwent lower extremity MRI to quantify muscle inflammation, replacement by fat, and disease asymmetry. Cardiac MRI, functional ability, muscle symptoms, and serum creatine kinase levels were also evaluated. RESULTS: Six pediatric females with dystrophinopathy (mean age: 11.7 years), 11 adult females with dystrophinopathy (mean age: 41.3 years), and seven controls enrolled. The mean fat fraction was increased in females with dystrophinopathy compared to controls in the soleus (0.11 vs. 0.03, p = .0272) and vastus lateralis (0.16 vs. 0.03, p = .004). Magnetic resonance spectroscopy water T2, indicative of muscle inflammation, was elevated in the soleus and/or vastus lateralis in 11 of 17 individuals. North Star Ambulatory Assessment score was lower in the dystrophinopathy group compared to controls (29 vs. 34 points, p = .0428). From cardiac MRI, left ventricle T1 relaxation times were elevated in females with dystrophinopathy compared to controls (1311 ± 55 vs. 1263 ± 25 ms, p < .05), but ejection fraction and circumferential strain did not differ. DISCUSSION: Symptomatic females with dystrophinopathy quantitatively demonstrate muscle replacement by fat and inflammation, along with impairments in functional ability and cardiac function. Additional research is needed to evaluate how symptoms and muscle involvement change longitudinally.
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Delivery represents a major hurdle to the clinical advancement of oligonucleotide therapeutics for the treatment of disorders such as Duchenne muscular dystrophy (DMD). In this preliminary study, we explored the ability of 2'-O-methyl-phosphorothioate antisense oligonucleotides (ASOs) conjugated with lipophilic ursodeoxycholic acid (UDCA) to permeate across intestinal barriers in vitro by a co-culture system of non-contacting IEC-6 cells and DMD myotubes, either alone or encapsulated in exosomes. UDCA was used to enhance the lipophilicity and membrane permeability of ASOs, potentially improving oral bioavailability. Exosomes were employed due to their biocompatibility and ability to deliver therapeutic cargo across biological barriers. Exon skipping was evaluated in the DMD myotubes to reveal the targeting efficiency. Exosomes extracted from milk and wild-type myotubes loaded with 5'-UDC-3'Cy3-ASO and seeded directly on DMD myotubes appear able to fuse to myotubes and induce exon skipping, up to ~20%. Permeation studies using the co-culture system were performed with 5'-UDC-3'Cy3-ASO 51 alone or loaded in milk-derived exosomes. In this setting, only gymnotic delivery induced significant levels of exon skipping (almost 30%) implying a possible role of the intestinal cells in enhancing delivery of ASOs. These results warrant further investigations to elucidate the delivery of ASOs by gymnosis or exosomes.
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We studied the effect of enteral administration of the glucocorticoid deflazacort (DFC, 1.2 mg/kg per day, 28 days) on the state of skeletal muscles and tissue ultrastructure, as well as the composition of the colon microbiota in dystrophin-deficient mdx mice. DFC has been shown to reduce the intensity of degeneration/regeneration cycles in muscle fibers of mdx mice. This effect of DFC was accompanied by normalization of the size of sarcomeres of skeletal muscles of mdx mice, improvement of the ultrastructure of the subsarcolemmal population of mitochondria, and an increase in the number of organelles, as well as normalization of the number of contact interactions between the sarcoplasmic reticulum and mitochondria. In addition, DFC had a corrective effect on the colon microbiota of mdx mice, which manifested in an increase in the number of the Bifidobacterium genus microorganisms and a decrease in the level of E. coli with reduced enzymatic activity.
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Colon , Microbioma Gastrointestinal , Glucocorticoides , Ratones Endogámicos mdx , Músculo Esquelético , Pregnenodionas , Animales , Ratones , Colon/efectos de los fármacos , Colon/microbiología , Colon/patología , Colon/ultraestructura , Pregnenodionas/farmacología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/ultraestructura , Músculo Esquelético/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Glucocorticoides/farmacología , Distrofina/genética , Distrofina/deficiencia , Distrofina/metabolismo , Bifidobacterium/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/ultraestructura , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Mitocondrias/efectos de los fármacos , Mitocondrias/ultraestructuraRESUMEN
Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive degenerative disease of skeletal muscle, characterized by intramuscular inflammation, muscle regeneration disorder and replacement of muscle with fibroadipose tissue. DMD is caused by the absence of normal dystrophy. Impaired self-renew ability and limited differentiation capacity of satellite cells are proved as main reasons for muscle regeneration failure. The deficiency of estrogen impedes the process of muscle regeneration. However, the role of estrogen receptor ß (ERß) in muscle regeneration is still unclear. This study aims to investigate the role and the pharmacological effect of ERß activation on muscle regeneration in mdx mice. This study showed that mRNA levels of ERß and myogenic-related genes both witnessed increasing trends in dystrophic context. Our results revealed that treatment with selective ERß agonist (DPN, diarylpropionitrile) significantly increased myogenic differentiation 1 (MyoD-1) level and promoted muscle regeneration in mdx mice. Similarly, in mdx mice with muscle-specific estrogen receptor α (ERα) ablation, DPN treatment still promoted muscle regeneration. Moreover, we demonstrated that myoblasts differentiation was accompanied by raised nuclear accumulation of ERß. DPN treatment augmented the nuclear accumulation of ERß and, thus, contributed to myotubes formation. One important finding was that forkhead box O3A (FOXO3A), as a pivotal transcription factor in Myod-1 transcription, participated in the ERß-promoted muscle regeneration. Overall, we offered an interesting explanation about the crucial role of ERß during myogenesis.
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The repurposing of RNA-programmable CRISPR systems from genome editing into epigenome editing tools is gaining pace, including in research and development efforts directed at tackling human disorders. This momentum stems from the increasing knowledge regarding the epigenetic factors and networks underlying cell physiology and disease etiology and from the growing realization that genome editing principles involving chromosomal breaks generated by programmable nucleases are prone to unpredictable genetic changes and outcomes. Hence, engineered CRISPR systems are serving as versatile DNA-targeting scaffolds for heterologous and synthetic effector domains that, via locally recruiting transcription factors and chromatin remodeling complexes, seek interfering with loss-of-function and gain-of-function processes underlying recessive and dominant disorders, respectively. Here, after providing an overview about epigenetic drugs and CRISPR-Cas-based activation and interference platforms, we cover the testing of these platforms in the context of molecular therapies for muscular dystrophies. Finally, we examine attributes, obstacles, and deployment opportunities for CRISPR-based epigenetic modulating technologies.
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Caveolin is a structural protein within caveolae that may be involved in transmembrane molecular transport and/or various intercellular interactions within cells. Specific mutations of caveolin-3 in muscle fibers are well known to cause limb-girdle muscular dystrophy. Altered expression of caveolin-3 has also been detected in Duchenne muscular dystrophy, which may be a part of the pathological process leading to muscle weakness. Interestingly, it has been shown that the renovation of nitric oxide synthase (NOS) in sarcolemma with muscular dystrophy could improve muscle health, suggesting that NOS may be involved in the pathology of muscular dystrophy. Here, we summarize the notable function of caveolin and/or NOS in skeletal muscle fibers and discuss their involvement in the pathology as well as possible tactics for the innovative treatment of muscular dystrophies.
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Caveolina 3 , Distrofias Musculares , Óxido Nítrico Sintasa , Animales , Humanos , Caveolas/metabolismo , Caveolina 3/metabolismo , Caveolina 3/genética , Caveolinas/metabolismo , Distrofias Musculares/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/patología , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patología , Mutación , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa/genéticaRESUMEN
OBJECTIVES: Quality-adjusted life years (QALYs) have been challenged as a measure of benefit for people with disabilities, particularly for those in low-utility health states or with irreversible disability. This study examined the impact of a QALY-based assessment on the price for a hypothetical treatment for Duchenne muscular dystrophy (DMD), a progressive, genetic neuromuscular disease. METHODS: A previously published, 5-state model, which analyzed treatments for early ambulatory (EA) DMD patients, was replicated, validated, and adapted to include early nonambulatory (ENA) DMD patients. The model was used to assess a QALY-based threshold price (maximum cost-effective price) for a hypothetical treatment for 13-year-old ENA and 5-year-old EA patients (initial health states with lower and higher utility, respectively). All inputs were replicated including willingness-to-pay thresholds of $50 000 to $200 000/QALY. RESULTS: In contrast to EA patients, ENA patients had a 98% modeled decline in QALY-based threshold price at a willingness-to-pay of $150 000/QALY or higher, despite equal treatment benefit (delayed progression/death). At $100 000/QALY or lower, net nontreatment costs exceeded health benefits, implying any treatment for ENA patients would not be considered cost-effective, even at $0 price, including an indefinite pause in disease progression. CONCLUSIONS: For certain severe, disabling conditions, traditional approaches are likely to conclude that treatments are not cost-effective at any price once a patient progresses to a disabled health state with low utility value. These findings elucidate theoretical/ethical concerns regarding potential discriminatory properties of traditional QALY assessments for people with disabilities, particularly those who have lost ambulation or have other physical limitations.
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Skeletal muscle fibrosis is defined as the excessive accumulation of extracellular matrix (ECM) components and is a hallmark of muscular dystrophies. Fibro-adipogenic progenitors (FAPs) are the main source of ECM, and thus have been strongly implicated in fibrogenesis. In skeletal muscle fibrotic models, including muscular dystrophies, FAPs undergo dysregulations in terms of proliferation, differentiation, and apoptosis, however few studies have explored the impact of FAPs migration. Here, we studied fibroblast and FAPs migration and identified lysophosphatidic acid (LPA), a signaling lipid central to skeletal muscle fibrogenesis, as a significant migration inductor. We identified LPA receptor 1 (LPA1) mediated signaling as crucial for this effect through a mechanism dependent on the Hippo pathway, another pathway implicated in fibrosis across diverse tissues. This cross-talk favors the activation of the Yes-associated protein 1 (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ), leading to increased expression of fibrosis-associated genes. This study reveals the role of YAP in LPA-mediated fibrotic responses as inhibition of YAP transcriptional coactivator activity hinders LPA-induced migration in fibroblasts and FAPs. Moreover, we found that FAPs derived from the mdx4cv mice, a murine model of Duchenne muscular dystrophy, display a heightened migratory phenotype due to enhanced LPA signaling compared to wild-type FAPs. Remarkably, we found that the inhibition of LPA1 or YAP transcriptional coactivator activity in mdx4cv FAPs reverts this phenotype. In summary, the identified LPA-LPA1-YAP pathway emerges as a critical driver of skeletal muscle FAPs migration and provides insights into potential novel targets to mitigate fibrosis in muscular dystrophies.
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Proteínas Adaptadoras Transductoras de Señales , Movimiento Celular , Fibroblastos , Fibrosis , Lisofosfolípidos , Músculo Esquelético , Receptores del Ácido Lisofosfatídico , Transducción de Señal , Proteínas Señalizadoras YAP , Lisofosfolípidos/metabolismo , Animales , Proteínas Señalizadoras YAP/metabolismo , Proteínas Señalizadoras YAP/genética , Ratones , Receptores del Ácido Lisofosfatídico/metabolismo , Receptores del Ácido Lisofosfatídico/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Fibroblastos/metabolismo , Fibroblastos/patología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Humanos , Vía de Señalización Hippo , Ratones Endogámicos mdx , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/metabolismo , Adipogénesis/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/patologíaRESUMEN
BACKGROUND AND AIMS: Although aerobic exercises such as cycling and swimming are increasingly being recommended in Duchenne muscular dystrophy (DMD), their effect on gait and balance parameters is unclear. This study was aimed to investigate the effect of cycling training on balance and spatio-temporal gait parameters in children with DMD. METHODS: Ambulant children (age range: 6.17-11.33 years) were randomly divided into two groups: home-based exercise training applied in the control group (n = 12) while 12 weeks of supervised submaximal lower extremity cycling training in addition to home-based exercise training performed in the study group (n = 11). Gait and balance parameters were evaluated using the GAITRite electronic walkway system and the Bertec Balance Check Screener™, respectively. Assessments were applied before and after 12 weeks of training. RESULTS: The mean ages of the children in the study and control groups were 8.20 (SD:1.34) and 8.86 (SD:1.30) years, consecutively (p > 0.05). Considering the baseline values, the balance and spatio-temporal gait parameters of the children were similar except for the antero-posterior postural sway on the perturbed surface with eyes open (p > 0.05). There was a significant time x group interaction effect in favor of the study group for the antero-posterior postural sway of children on the normal surface with eyes open (F (1,58) = 12.62, p = 0.002). It was found that the antero-posterior postural sway on the normal surface with eyes open was improved in the study group within group comparison (F (1,10) = 8.50, p = 0.015). CONCLUSIONS: The study showed that both the cycling and the home-based exercise training groups may maintain gait and balance parameters during the study. Adding a cycling training to the rehabilitation program can also provide additional contribution to improve antero-posterior balance.
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Terapia por Ejercicio , Marcha , Distrofia Muscular de Duchenne , Equilibrio Postural , Humanos , Distrofia Muscular de Duchenne/rehabilitación , Distrofia Muscular de Duchenne/fisiopatología , Niño , Equilibrio Postural/fisiología , Masculino , Terapia por Ejercicio/métodos , Marcha/fisiología , Femenino , Ciclismo/fisiología , Resultado del TratamientoRESUMEN
PURPOSE: The aim of this study was to examine the cognitive and emotional-behavioural outcomes of Turkish children with Duchenne muscular dystrophy (DMD) in comparison with healthy peers, to determine its relationship with motor functions, and to analyse the difference of cognitive and emotional-behavioural outcomes according to the site of mutations. METHOD: Children aged 7-16 years with DMD (n = 68) and age-matched typically developing children (n = 33) were included in the study. The cognitive and emotional-behavioural status and the motor functions were assessed in detail. Children with DMD also divided into two groups as "proximal" and "distal" site mutation groups to compare the cognitive and emotional-behavioural outcomes. RESULTS: The children with DMD and typically developing children were similar in terms of age and body mass index (p > 0.05). Significant differences were found between children with DMD and typically developing peers in almost all subtests of both cognitive and emotional-behavioural assessments (p < 0.05). Cognitive and emotional-behavioural parameters were weakly correlated with specific motor parameters responsive to cognitive functioning (p < 0.05). Children with distal site mutation performed significantly worser than those with proximal site mutation in particular cognitive subtest (p < 0.05). CONCLUSIONS: It is concluded that comprehensive and detailed evaluation of cognitive and emotional-behavioural features of children with DMD is essential for better implementation of rehabilitation programs to maintain motor function which especially requires cognitive ability, since a Turkish cohort represented challenges in particular domains of cognitive and emotional-behavioural areas. CLINICAL TRIAL REGISTRATION NUMBER: NCT05661071.
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Distrofia Muscular de Duchenne , Humanos , Distrofia Muscular de Duchenne/psicología , Distrofia Muscular de Duchenne/fisiopatología , Niño , Masculino , Adolescente , Turquía/epidemiología , Femenino , Emociones/fisiología , Cognición/fisiología , Pruebas Neuropsicológicas , MutaciónRESUMEN
Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle degenerative disease, caused by mutations in the dystrophin gene and resulting in premature death. As a major secondary event, an abnormal elevation of the intracellular calcium concentration in the dystrophin-deficient muscle contributes to disease progression in DMD. In this study, we investigated the specific functional features of induced pluripotent stem cell-derived muscle cells (hiPSC-skMCs) generated from DMD patients to regulate intracellular calcium concentration. As compared to healthy hiPSC-skMCs, DMD hiPSC-skMCs displayed specific spontaneous calcium signatures with high levels of intracellular calcium concentration. Furthermore, stimulations with electrical field or with acetylcholine perfusion induced higher calcium response in DMD hiPSC-skMCs as compared to healthy cells. Finally, Mn2+ quenching experiments demonstrated high levels of constitutive calcium entries in DMD hiPSC-skMCs as compared to healthy cells. Our findings converge on the fact that DMD hiPSC-skMCs display intracellular calcium dysregulation as demonstrated in several other models. Observed calcium disorders associated with RNAseq analysis on these DMD cells highlighted some mechanisms, such as spontaneous and activated sarcoplasmic reticulum (SR) releases or constitutive calcium entries, known to be disturbed in other dystrophin-deficient models. However, store operated calcium entries (SOCEs) were not found to be dysregulated in our DMD hiPSC-skMCs model. These results suggest that all the mechanisms of calcium impairment observed in other animal models may not be as pronounced in humans and could point to a preference for certain mechanisms that could correspond to major molecular targets for DMD therapies.
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Calcio , Células Madre Pluripotentes Inducidas , Distrofia Muscular de Duchenne , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Humanos , Calcio/metabolismo , Señalización del Calcio , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Diferenciación Celular , Células Cultivadas , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Retículo Sarcoplasmático/metabolismoRESUMEN
Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder affecting 1:3500 male births and is associated with myofiber degeneration, regeneration, and inflammation. Glucocorticoid treatments have been the standard of care due to immunomodulatory/immunosuppressive properties but novel genetic approaches, including exon skipping and gene replacement therapy, are currently being developed. The identification of additional biomarkers to assess DMD-related inflammatory responses and the potential efficacy of these therapeutic approaches are thus of critical importance. The current study uses RNA sequencing of skeletal muscle from two mdx mouse models to identify high mobility group box 1 (HMGB1) as a candidate biomarker potentially contributing to DMD-related inflammation. HMGB1 protein content was increased in a human iPSC-derived skeletal myocyte model of DMD and microdystrophin treatment decreased HMGB1 back to control levels. In vivo, HMGB1 protein levels were increased in vehicle treated B10-mdx skeletal muscle compared to B10-WT and significantly decreased in B10-mdx animals treated with adeno-associated virus (AAV)-microdystrophin. However, HMGB1 protein levels were not increased in D2-mdx skeletal muscle compared to D2-WT, demonstrating a strain-specific difference in DMD-related immunopathology.
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Biomarcadores , Proteína HMGB1 , Distrofia Muscular de Duchenne , Animales , Humanos , Masculino , Ratones , Modelos Animales de Enfermedad , Distrofina/metabolismo , Distrofina/genética , Proteína HMGB1/metabolismo , Proteína HMGB1/genética , Células Madre Pluripotentes Inducidas/metabolismo , Ratones Endogámicos mdx , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/genéticaRESUMEN
Dystrophinopathies are a group of neuromuscular disorders, inherited in an X-linked recessive manner, caused by pathogenic variants in the DMD gene. Copy number variation detection and next generation sequencing allow the detection of around 99 % of the pathogenic variants. However, some patients require mRNA studies from muscle biopsies to identify deep intronic pathogenic variants. Here, we report a child suspected of having Duchenne muscular dystrophy, with a muscle biopsy showing dystrophin deficiency, and negative molecular testing for deletions, duplications, and small variants. mRNA analysis from muscle biopsy revealed a pseudoexon activation that introduce a premature stop codon into the reading frame. gDNA sequencing allowed to identified a novel variant, c.832-186 T>G, which creates a cryptic donor splice site, recognizing the underlying mechanism causing the pseudoexon insertion. This case highlights the usefulness of the mRNA analysis from muscle biopsy when routine genetic testing is negative and clinical suspicion of dystrophinopathies remains the main clinical diagnosis suspicion.