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Medical management of muscle weakness in Duchenne muscular dystrophy.

ABSTRACT: INTRODUCTION:Duchenne muscular dystrophy (DMD) is a childhood onset muscular dystrophy leading to shortened life expectancy. There are gaps in published DMD care guidelines regarding recently approved DMD medications and alternative steroid dosing regimens. METHODS:A list of statements about use of currently available therapies for DMD in the United States was developed based on a systematic literature review and expert panel feedback. Panelists' responses were collected using a modified Delphi approach. RESULTS:Among corticosteroid regimens, either deflazacort or prednisone weekend dosing was preferred when payer requirements do not dictate choice. Most patients with exon 51 skip-amenable mutations should be offered eteplirsen, before or with a corticosteroid. DISCUSSION:The options available for medical management of the motor symptoms of DMD are expanding rapidly. The choice of medical therapies should balance expected benefit with side effects.

SUBMITTER: Rivera SR

PROVIDER: S-EPMC7571693 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Medical management of muscle weakness in Duchenne muscular dystrophy.

Rivera Sarah R SR Jhamb Sumit K SK Abdel-Hamid Hoda Z HZ Acsadi Gyula G Brandsema John J Ciafaloni Emma E Darras Basil T BT Iannaccone Susan T ST Konersman Chamindra G CG Kuntz Nancy L NL McDonald Craig M CM Parsons Julie A JA Tesi Rocha Carolina C Zaidman Craig M CM Butterfield Russell J RJ Connolly Anne M AM Mathews Katherine D KD

PloS one 20201019 10

<h4>Introduction</h4>Duchenne muscular dystrophy (DMD) is a childhood onset muscular dystrophy leading to shortened life expectancy. There are gaps in published DMD care guidelines regarding recently approved DMD medications and alternative steroid dosing regimens.<h4>Methods</h4>A list of statements about use of currently available therapies for DMD in the United States was developed based on a systematic literature review and expert panel feedback. Panelists' responses were collected using a m ...[more]

PMID: 33075081

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Project description:Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy caused by mutations in the dystrophin gene. Loss of dystrophin initiates a progressive decline in skeletal muscle integrity and contractile capacity which weakens respiratory muscles including the diaphragm, culminating in respiratory failure, the leading cause of morbidity and mortality in DMD patients. At present, corticosteroid treatment is the primary pharmacological intervention in DMD, but has limited efficacy and adverse side effects. Thus, there is an urgent need for new safe, cost-effective, and rapidly implementable treatments that slow disease progression. One promising new approach is the amplification of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signalling pathways with phosphodiesterase 5 (PDE5) inhibitors. PDE5 inhibitors serve to amplify NO signalling that is attenuated in many neuromuscular diseases including DMD. We report here that a 14-week treatment of the mdx mouse model of DMD with the PDE5 inhibitor sildenafil (Viagra(®), Revatio(®)) significantly reduced mdx diaphragm muscle weakness without impacting fatigue resistance. In addition to enhancing respiratory muscle contractility, sildenafil also promoted normal extracellular matrix organization. PDE5 inhibition slowed the establishment of mdx diaphragm fibrosis and reduced matrix metalloproteinase-13 (MMP-13) expression. Sildenafil also normalized the expression of the pro-fibrotic (and pro-inflammatory) cytokine tumour necrosis factor α (TNFα). Sildenafil-treated mdx diaphragms accumulated significantly less Evans Blue tracer dye than untreated controls, which is also indicative of improved diaphragm muscle health. We conclude that sildenafil-mediated PDE5 inhibition significantly reduces diaphragm respiratory muscle dysfunction and pathology in the mdx mouse model of Duchenne muscular dystrophy. This study provides new insights into the therapeutic utility of targeting defects in NO-cGMP signalling with PDE5 inhibitors in dystrophin-deficient muscle.

Project description:BACKGROUND:Performing daily activities independently becomes more difficult in time for patients with Duchenne muscular dystrophy (DMD) due to muscle weakness. When performing seated daily activities, the trunk plays an indispensable role besides the upper extremities. However, knowledge is lacking on the interaction between trunk and upper extremities. Therefore the aim was to investigate whether patients with DMD use trunk movement to compensate for reduced arm function when performing seated tasks, and whether this is related to increased muscle activity. METHODS:Eighteen boys with DMD and twenty-five healthy controls (HC) performed several tasks when sitting unsupported, like reaching (and placing) forward and sideward, drinking and displacing a dinner plate. Maximum joint torque and maximum surface electromyography (sEMG) were measured during maximum voluntary isometric contractions. Three-dimensional movements and normalized sEMG when performing tasks were analyzed. RESULTS:Significantly decreased maximum joint torque was found in DMD patients compared to HC. Trunk and shoulder torques were already decreased in early disease stages. However, only maximum trunk rotation and shoulder abduction torque showed a significant association with Brooke scale. In all reaching and daily tasks, the range of motion in lateral bending and/or flexion-extension was significantly larger in DMD patients compared to HC. The trunk movements did not significantly increase with task difficulty (e.g. increasing object weight) or Brooke scale. Normalized muscle activity was significantly higher in DMD patients for all tasks and muscles. CONCLUSIONS:Boys with DMD use increased trunk movements to compensate for reduced arm function, even when performing relatively simple tasks. This was combined with significantly increased normalized muscle activity. Clinicians should take the trunk into account when assessing function and for intervention development, because DMD patients may appear to have a good trunk function, but percentage of muscle capacity used to perform tasks is increased.

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Medical management of muscle weakness in Duchenne muscular dystrophy.

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Medical management of muscle weakness in Duchenne muscular dystrophy.

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