Noninvasive evaluation of respiratory muscles in pre-clinical model of Duchenne Muscular Dystrophy

Abstract Since respiratory insufficiency is the main cause of death in patients affected by Duchenne Muscular Dystrophy (DMD), the present study aims at establishing a new non-invasive method to evaluate the clinical parameters of respiratory conditions of experimental models affected by DMD. With this purpose in mind, we evaluated the cardiorespiratory clinical conditions, the changes in the intercostal muscles, the diaphragmatic mobility, and the respiratory cycles in Golden Retriever Muscular Dystrophy (GRMD) employing ultrasonography (US). A control group consisting of dogs of the same race, but not affected by muscular dystrophy, were used in this study. The results showed that inspiration, expiration and plateau movements (diaphragm mobility) were lower in the affected group. Plateau phase in the affected group was practically non-existent and showed that the diaphragm remained in constant motion. Respiratory rate reached 15.5 per minute for affected group and 26.93 per minute for the control group. Expiration and inspiration movements of intercostal muscles reached 8.99mm and 8.79mm, respectively, for control group and 7.42mm and 7.40mm, respectively, for affected group. Methodology used in the present analysis proved to be viable for the follow-up and evaluation of the respiratory model in GRMD and may be adapted to other muscular dystrophy experimental models.

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Open-Label Evaluation of Eteplirsen in Patients with Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping: PROMOVI Trial

Journal of Neuromuscular Diseases ◽

10.3233/jnd-210643 ◽

2021 ◽

pp. 1-13

Author(s):

Craig M. McDonald ◽

Perry B. Shieh ◽

Hoda Z. Abdel-Hamid ◽

Anne M. Connolly ◽

Emma Ciafaloni ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Natural History ◽

Adverse Events ◽

Exon Skipping ◽

Control Group ◽

Phase 2 ◽

Open Label ◽

M Phase ◽

Positive Treatment

Background Eteplirsen received accelerated FDA approval for treatment of Duchenne muscular dystrophy (DMD) with mutations amenable to exon 51 skipping, based on demonstrated dystrophin production. Objective To report results from PROMOVI, a phase 3, multicenter, open-label study evaluating efficacy and safety of eteplirsen in a larger cohort. Methods Ambulatory patients aged 7–16 years, with confirmed mutations amenable to exon 51 skipping, received eteplirsen 30 mg/kg/week intravenously for 96 weeks. An untreated cohort with DMD not amenable to exon 51 skipping was also enrolled. Results 78/79 eteplirsen-treated patients completed 96 weeks of treatment. 15/30 untreated patients completed the study; this cohort was considered an inappropriate control group because of genotype-driven differences in clinical trajectory. At Week 96, eteplirsen-treated patients showed increased exon skipping (18.7-fold) and dystrophin protein (7-fold) versus baseline. Post-hoc comparisons with patients from eteplirsen phase 2 studies (4658-201/202) and mutation-matched external natural history controls confirmed previous results, suggesting clinically notable attenuation of decline on the 6-minute walk test over 96 weeks (PROMOVI: –68.9 m; phase 2 studies: –67.3 m; external controls: –133.8 m) and significant attenuation of percent predicted forced vital capacity annual decline (PROMOVI: –3.3%, phase 2 studies: –2.2%, external controls: –6.0%; p < 0.001). Adverse events were generally mild to moderate and unrelated to eteplirsen. Most frequent treatment-related adverse events were headache and vomiting; none led to treatment discontinuation. Conclusions This large, multicenter study contributes to the growing body of evidence for eteplirsen, confirming a positive treatment effect, favorable safety profile, and slowing of disease progression versus natural history.

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Autonomic modulation at rest and in response to postural change in adolescents with Duchenne muscular dystrophy: a cross-sectional study

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x-anp-2020-0458 ◽

2021 ◽

Vol 79 (9) ◽

pp. 766-773

Author(s):

Mariana Viana Rodrigues ◽

Mileide Cristina Stoco-Oliveira ◽

Talita Dias da Silva ◽

Celso Ferreira ◽

Heloisa Balotari Valente ◽

...

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Oxygen Saturation ◽

Cross Sectional Study ◽

Control Group ◽

Autonomic Modulation ◽

Postural Change ◽

Cross Sectional

ABSTRACT Background: Analysis of autonomic modulation after postural change may inform the prognosis and guide treatment in different populations. However, this has been insufficiently explored among adolescents with Duchenne muscular dystrophy (DMD). Objective: To investigate autonomic modulation at rest and in response to an active sitting test (AST) among adolescents with DMD. Methods: Fifty-nine adolescents were included in the study and divided into two groups: 1) DMD group: adolescents diagnosed with DMD; 2) control group (CG): healthy adolescents. Participants’ weight and height were assessed. Lower limb function, motor limitations and functional abilities of the participants in the DMD group were classified using the Vignos scale, Egen classification and motor function measurement, respectively. The following variables were assessed before, during and after AST: systolic blood pressure (SBP), diastolic blood pressure (DBP), respiratory rate (f), oxygen saturation and heart rate (HR). To analyze the autonomic modulation, the HR was recorded beat-by-beat. Heart rate variability (HRV) indices were calculated in the time and frequency domains. Results: Differences in relation to groups were observed for all HRV indices, except LF/HF, oxygen saturation, HR and f (p < 0.05). Differences in relation to time and the interaction effect between group and time were observed for RMSSD, SD1, SD2, SD1/SD2, LFms2 and LFnu, HFun, SBP and DBP (p < 0.05). Differences in relation to time were also observed for the indice SDNN, FC and f (p < 0.05). Conclusions: Performing the AST promoted reduced autonomic modulation and increased SBP, DBP and HR in adolescents with DMD.

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Mast cells in the pathophysiology of Duchenne muscular dystrophy in Golden Retriever dogs

Pesquisa Veterinária Brasileira ◽

10.1590/1678-5150-pvb-6340 ◽

2020 ◽

Vol 40 (10) ◽

pp. 791-797

Author(s):

Isabela M. Martins ◽

Lygia M.M. Malvestio ◽

Jair R. Engracia-Filho ◽

Gustavo S. Claudiano ◽

Flávio R. Moraes ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Mast Cells ◽

Muscular Dystrophy ◽

Fibrous Tissue ◽

Control Group ◽

Golden Retriever ◽

Collagenous Tissue ◽

Muscle Types ◽

Muscle Groups

ABSTRACT: The Golden Retriever muscular dystrophy (GRMD) is one of the best models of Duchenne muscular dystrophy (DMD), with similar genotypic and phenotypic manifestations. Progressive proliferation of connective tissue in the endomysium of the muscle fibers occurs in parallel with the clinical course of the disease in GRMD animals. Previous studies suggest a relationship between mast cells and the deposition of fibrous tissue due to the release of mediators that recruit fibroblasts. The aim of this study was to evaluate the presence of mast cells and their relationship with muscle injury and fibrosis in GRMD dogs of different ages. Samples of muscle groups from six GRMD and four control dogs, aged 2 to 8 months, were collected and analyzed. The samples were processed and stained with HE, toluidine blue, and Azan trichrome. Our results showed that there was a significant increase in infiltration of mast cells in all muscle groups of GRMD dogs compared to the control group. The average number of mast cells, as well as the deposition of fibrous tissue, decreased with age in GRMD dogs. In the control group, all muscle types showed a significant increase in the amount of collagenous tissue. This suggests increased mast cell degranulation occurred in younger GRMD dogs, resulting in increased interstitial space and fibrous tissue in muscle, which then gradually decreased over time as the dogs aged. However, further studies are needed to clarify the role of mast cells in the pathogenesis of fibrosis.

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Validation of Chemokine Biomarkers in Duchenne Muscular Dystrophy

Life ◽

10.3390/life11080827 ◽

2021 ◽

Vol 11 (8) ◽

pp. 827

Author(s):

Michael Ogundele ◽

Jesslyn S. Zhang ◽

Mansi V. Goswami ◽

Marissa L. Barbieri ◽

Utkarsh J. Dang ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Early Stage ◽

Wild Type Mouse ◽

Muscle Disease ◽

Mdx Mouse ◽

Control Group ◽

P Value ◽

Glucocorticoid Treatment

Duchenne muscular dystrophy (DMD) is a progressive muscle disease involving complex skeletal muscle pathogenesis. The pathogenesis is triggered by sarcolemma instability due to the lack of dystrophin protein expression, leading to Ca2+ influx, muscle fiber apoptosis, inflammation, muscle necrosis, and fibrosis. Our lab recently used two high-throughput multiplexing techniques (e.g., SomaScan® aptamer assay and tandem mass tag-(TMT) approach) and identified a series of serum protein biomarkers tied to different pathobiochemical pathways. In this study, we focused on validating the circulating levels of three proinflammatory chemokines (CCL2, CXCL10, and CCL18) that are believed to be involved in an early stage of muscle pathogenesis. We used highly specific and reproducible MSD ELISA assays and examined the association of these chemokines with DMD pathogenesis, age, disease severity, and response to glucocorticoid treatment. As expected, we confirmed that these three chemokines were significantly elevated in serum and muscle samples of DMD patients relative to age-matched healthy controls (p-value < 0.05, CCL18 was not significantly altered in muscle samples). These three chemokines were not significantly elevated in Becker muscular dystrophy (BMD) patients, a milder form of dystrophinopathy, when compared in a one-way ANOVA to a control group but remained significantly elevated in the age-matched DMD group (p < 0.05). CCL2 and CCL18 but not CXCL10 declined with age in DMD patients, whereas all three chemokines remained unchanged with age in BMD and controls. Only CCL2 showed significant association with time to climb four steps in the DMD group (r = 0.48, p = 0.038) and neared significant association with patients’ reported outcome in the BMD group (r = 0.39, p = 0.058). Furthermore, CCL2 was found to be elevated in a serum of the mdx mouse model of DMD, relative to wild-type mouse model. This study suggests that CCL2 might be a suitable candidate biomarker for follow-up studies to demonstrate its physiological significance and clinical utility in DMD.

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Event-related potentials (P300) and neuropsychological assessment in boys exhibiting Duchenne muscular dystrophy

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2007000100013 ◽

2007 ◽

Vol 65 (1) ◽

pp. 59-62 ◽

Cited By ~ 5

Author(s):

Marcus Vinicius Della Coletta ◽

Rosana Herminia Scola ◽

Gislaine Richter Minhoto Wiemes ◽

Cláudia Nasser Fonseca ◽

Maria Joana Mäder ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Neuropsychological Test ◽

Event Related Potentials ◽

Poor Performance ◽

Control Group ◽

Test Results ◽

Neuropsychological Dysfunction ◽

P300 Potentials ◽

Related Potentials

OBJECTIVE: To examine auditory cognitive evoked potentials (P300 potentials) and neuropsychological dysfunction in patients with Duchenne muscular dystrophy (DMD). METHOD: P300 potentials and neuropsychological test results were obtained from 16 healthy control boys and 20 DMD patients. Full Intelligence Quotients (IQ) were estimated for patients and control group. Mean age was 9.5 years in the DMD patient group, and 10 years in the control group (p>0.05). RESULTS: The mean IQ values were 64.35 in the DMD patients and 82.68 in the control group (p=0.01). Mean P300 values were 347.6 in the DMD group and 337.4 in the control group (p=0.14). There was no significant correlation between parameters in each group. CONCLUSION: DMD patients showed a poor performance as evaluated by P300 potential compared to the control group, although the difference was not statistically significant. Systematic alterations in neuropsychological test results were found, the differences paralleling those detected in IQ.

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A novel mouse model of Duchenne muscular dystrophy carrying a multi-exonic Dmd deletion exhibits progressive muscular dystrophy and early-onset cardiomyopathy

Disease Models & Mechanisms ◽

10.1242/dmm.045369 ◽

2020 ◽

Vol 13 (9) ◽

pp. dmm045369

Author(s):

Tatianna Wai Ying Wong ◽

Abdalla Ahmed ◽

Grace Yang ◽

Eleonora Maino ◽

Sydney Steiman ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Early Onset ◽

Treatment Strategies ◽

Clinical Model ◽

Life Threatening ◽

Cardiac Muscles ◽

Almost All ◽

The Impact

ABSTRACTDuchenne muscular dystrophy (DMD) is a life-threatening neuromuscular disease caused by the lack of dystrophin, resulting in progressive muscle wasting and locomotor dysfunctions. By adulthood, almost all patients also develop cardiomyopathy, which is the primary cause of death in DMD. Although there has been extensive effort in creating animal models to study treatment strategies for DMD, most fail to recapitulate the complete skeletal and cardiac disease manifestations that are presented in affected patients. Here, we generated a mouse model mirroring a patient deletion mutation of exons 52-54 (Dmd Δ52-54). The Dmd Δ52-54 mutation led to the absence of dystrophin, resulting in progressive muscle deterioration with weakened muscle strength. Moreover, Dmd Δ52-54 mice present with early-onset hypertrophic cardiomyopathy, which is absent in current pre-clinical dystrophin-deficient mouse models. Therefore, Dmd Δ52-54 presents itself as an excellent pre-clinical model to evaluate the impact on skeletal and cardiac muscles for both mutation-dependent and -independent approaches.

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Boys With Duchenne Muscular Dystrophy: 1-Year Locomotor Changes in Relation to a Control Group

Perceptual and Motor Skills ◽

10.1177/0031512517740684 ◽

2017 ◽

Vol 125 (1) ◽

pp. 40-56 ◽

Cited By ~ 4

Author(s):

Joyce Martini ◽

Fátima Aparecida Caromano ◽

Eduardo Vital Carvalho ◽

Priscila Albuquerque Goya ◽

Rosana Massae Hayasaka ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Control Group

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Targeting the respiratory muscles of fetal sheep for prenatal gene therapy for Duchenne muscular dystrophy

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2005.06.077 ◽

2005 ◽

Vol 193 (3) ◽

pp. 1105-1109 ◽

Cited By ~ 16

Author(s):

Boaz Weisz ◽

Anna L. David ◽

Lisa G. Gregory ◽

Dany Perocheau ◽

Ali Ruthe ◽

...

Keyword(s):

Gene Therapy ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Respiratory Muscles ◽

Fetal Sheep

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Influence of Different Types of Corticosteroids on Heart Rate Variability of Individuals with Duchenne Muscular Dystrophy—A Pilot Cross Sectional Study

Life ◽

10.3390/life11080752 ◽

2021 ◽

Vol 11 (8) ◽

pp. 752

Author(s):

Rodrigo Martins Dias ◽

Rosangela Akemi Hoshi ◽

Luiz Carlos Marques Vanderlei ◽

Carlos Bandeira de Mello Monteiro ◽

Mayra Priscila Boscolo Alvarez ◽

...

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Cross Sectional Study ◽

Control Group ◽

Autonomic Modulation ◽

Sectional Study ◽

Cross Sectional ◽

Cardiac Autonomic Modulation

Individuals with Duchenne Muscular Dystrophy (DMD) have an impairment of cardiac autonomic function categorized by parasympathetic reduction and sympathetic predominance. The objective of this study was to assess the cardiac autonomic modulation of individuals with DMD undergoing therapy with Prednisone/Prednisolone and Deflazacort and compare with individuals with DMD without the use of these medications and a typically developed control group. Methods: A cross-sectional study was completed, wherein 40 boys were evaluated. The four treatment groups were: Deflazacort; Prednisone/Prednisolone; no corticoid use; and typical development. Heart Rate Variability (HRV) was investigated via linear indices (Time Domain and Frequency Domain) and non-linear indices Results: The results of this study revealed that individuals with DMD undertaking pharmacotherapies with Prednisolone demonstrated HRV comparable to the Control Typically Developed (CTD) group. In contrast, individuals with DMD undergoing pharmacotherapies with Deflazacort achieved lower HRV, akin to individuals with DMD without any medications, as demonstrated in the metrics: RMSSD; LF (n.u.), HF (n.u.), LF/HF; SD1, α1, and α1/α2, and a significant effect for SD1/SD2; %DET and Ratio; Shannon Entropy, 0 V%, 2 LV% and 2 ULV%. Conclusions: Corticosteroids have the potential to affect the cardiac autonomic modulation in adolescents with DMD. The use of Prednisone/Prednisolone appears to promote improved responses in terms of sympathovagal activity as opposed to Deflazacort.

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The effect of trunk training on trunk control, upper extremity, and pulmonary function in children with Duchenne muscular dystrophy: A randomized clinical trial

Clinical Rehabilitation ◽

10.1177/02692155211043265 ◽

2021 ◽

pp. 026921552110432

Author(s):

Gökçe Yağmur Güneş Gencer ◽

Öznur Yilmaz

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Pulmonary Function ◽

Respiratory Function ◽

Exercise Program ◽

Control Group ◽

Study Group ◽

Trunk Control ◽

Intergroup Comparison ◽

Arm Function

Objectives: To investigate the effect of trunk training on trunk control, arm, and pulmonary function in children with Duchenne muscular dystrophy. Design: A randomised controlled trial. Settings: Neuromuscular diseases clinic of university hospital. Subjects: Twenty-six children with Duchenne muscular dystrophy aged 5–16 were included in the study. Intervention: Participants were randomly allocated into two groups. The study group ( N = 13) exercised with the trunk-oriented exercise program and the conventional exercise program, whereas the control group ( N = 13) underwent the conventional exercise program for eight weeks. Main measures: The primary outcomes were trunk control was assessed using the Trunk Control Measurement Scale, the arm function was assessed using Performance of Upper Limb, and respiratory function using the pulmonary function test. Data collection was conducted at baseline, and eighth week. The differences in trunk control scores, arm function scores, and respiratory function values before and after the training were calculated for the intergroup comparison. Results: The mean age of the participants was 11.6 (2.6) in the study group and 10.6 (3.4) in the control group. The changes between trunk control score, arm function score (total and distal level score), and respiratory function value (Forced Vital Capacity, Forced Expiratory Volume in one second, and Peak Expiratory Flow Volume percentage values) were compared and significant differences were found after eight week periods in the study and control groups. Conclusions: Trunk-oriented exercise program in Duchenne muscular dystrophy might be effective for trunk control, arm, and respiratory function.

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