Dataset Information

Autonomic Modulation in Duchenne Muscular Dystrophy during a Computer Task: A Prospective Control Trial.

ABSTRACT:

Introduction

Duchenne Muscular Dystrophy (DMD) is characterized by progressive muscle weakness that can lead to disability. Owing to functional difficulties faced by individuals with DMD, the use of assistive technology is essential to provide or facilitate functional abilities. In DMD, cardiac autonomic dysfunction has been reported in addition to musculoskeletal impairment. Consequently, the objective was to investigate acute cardiac autonomic responses, by Heart Rate Variability (HRV), during computer tasks in subjects with DMD.

Method

HRV was assessed by linear and nonlinear methods, using the heart rate monitor Polar RS800CX chest strap Electrocardiographic measuring device. Then, 45 subjects were included in the group with DMD and 45 in the healthy Typical Development (TD) control group. They were assessed for twenty minutes at rest sitting, and five minutes after undergoing a task on the computer.

Results

Individuals with DMD had a statistically significant lower parasympathetic cardiac modulation at rest when compared to the control group, which further declined when undergoing the tasks on the computer.

Conclusion

DMD patients presented decreased HRV and exhibited greater intensity of cardiac autonomic responses during computer tasks characterized by vagal withdrawal when compared to the healthy TD control subjects.

SUBMITTER: Alvarez MP

PROVIDER: S-EPMC5261738 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Autonomic Modulation in Duchenne Muscular Dystrophy during a Computer Task: A Prospective Control Trial.

Alvarez Mayra Priscila Boscolo MP Silva Talita Dias da TD Favero Francis Meire FM Valenti Vitor Engrácia VE Raimundo Rodrigo Daminello RD Vanderlei Luiz Carlos Marques LC Garner David M DM Monteiro Carlos Bandeira de Mello CB

PloS one 20170124 1

<h4>Introduction</h4>Duchenne Muscular Dystrophy (DMD) is characterized by progressive muscle weakness that can lead to disability. Owing to functional difficulties faced by individuals with DMD, the use of assistive technology is essential to provide or facilitate functional abilities. In DMD, cardiac autonomic dysfunction has been reported in addition to musculoskeletal impairment. Consequently, the objective was to investigate acute cardiac autonomic responses, by Heart Rate Variability (HRV) ...[more]

PMID: 28118369

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Project description:Duchenne muscular dystrophy (DMD), an X-linked childhood-onset muscular dystrophy caused by loss of the protein dystrophin, can be associated with neurodevelopmental, emotional and behavioural problems. A DMD mouse model also displays a neuropsychiatric phenotype, including increased startle responses to threat which normalise when dystrophin is restored in the brain. We hypothesised that startle responses may also be increased in humans with DMD, which would have potential translational therapeutic implications. To investigate this, we first designed a novel discrimination fear-conditioning task and tested it in six healthy volunteers, followed by male DMD (n = 11) and Control (n = 9) participants aged 7-12 years. The aims of this methodological task development study were to: i) confirm the task efficacy; ii) optimise data processing procedures; iii) determine the most appropriate outcome measures. In the task, two neutral visual stimuli were presented: one 'safe' cue presented alone; one 'threat' cue paired with a threat stimulus (aversive noise) to enable conditioning of physiological startle responses (skin conductance response, SCR, and heart rate). Outcomes were the unconditioned physiological startle responses to the initial threat, and retention of conditioned responses in the absence of the threat stimulus. We present the protocol development and optimisation of data processing methods based on empirical data. We found that the task was effective in producing significantly higher physiological startle SCR in reinforced 'threat' trials compared to 'safe' trials (P < .001). Different data extraction methods were compared and optimised, and the optimal sampling window was derived empirically. SCR amplitude was the most effective physiological outcome measure when compared to SCR area and change in heart rate, with the best profile on data processing, the least variance, successful conditioned response retention (P = .01) and reliability assessment in test-retest analysis (rho = .86). The definition of this novel outcome will allow us to study this response in a DMD population.

Project description:BackgroundCurrently, the most promising therapies for Duchenne muscular dystrophy (DMD) are exon skipping and stop codon read-through, two strategies aimed at restoring the expression of dystrophin. A phase 3 clinical trial with drisapersen, a drug designed to induce exon 51-skipping, has failed to show significant improvement of the primary outcome measure, the six-minute walk test.DiscussionHere, we review some key points that should be considered when designing clinical trials for these new therapies. First, younger patients have more functional abilities and more muscle fibers to preserve than older patients and therefore are better subjects for trials designed to demonstrate the success of new treatments. Second, the inclusion of patients on corticosteroids both in the treatment and placebo groups is of concern because the positive effect of corticosteroids might mask the effect of the treatment being tested. Additionally, the reasonable expectation from these therapies is the slowing of disease progression rather than improvement. Therefore, the appropriate clinical endpoints are the prolongation of the ability to stand from the floor, climb stairs, and walk, not an increase in muscle strength or function. Hence, the time frames for the detection of new dystrophin, which occurs within months, and the ability to demonstrate a slowing of disease progression, which requires years, are strikingly different. Finally, placebo-controlled trials are difficult to manage if years of blindness are required to demonstrate a slowing of disease progression. Thus, accelerated/conditional approval for new therapies should be based on surrogate biochemical outcomes: the demonstration of de novo dystrophin production and of its beneficial effect on the functional recovery of muscle fiber. These data suggest that clinical trials for DMD patients must be adapted to the particular characteristics of the disease in order to demonstrate the expected positive effect of new treatments.

Project description:Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA's metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.

Dataset Information

Autonomic Modulation in Duchenne Muscular Dystrophy during a Computer Task: A Prospective Control Trial.

Introduction

Method

Results

Conclusion

Publications

Autonomic Modulation in Duchenne Muscular Dystrophy during a Computer Task: A Prospective Control Trial.

Similar Datasets

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