Muscular Dystrophies

Limb girdle muscular dystrophy type 2A (LGMD2A) is caused by mutations in the calpain 3 gene. In a large family affected by LGMD2A with four severely affected members, three additional asymptomatic relatives had very high serum creatine kinase concentrations. All were homozygous for the R110X mutation and showed a total absence of calpain 3 in the muscle. Histological analysis of

The first generation of troponin T ELISA (TnT 1) can yield false-positive results in patients with severe skeletal muscle injury. Therefore, a cardiac-specific second-generation troponin T ELISA (TnT 2) was developed, in which the cross-reactive antibody 1B10 has been replaced by a high-affinity cardiac-specific antibody M11.7. No cross-reactivity of TnT 2 was observed with purified skeletal muscle troponin T (1000 micrograms/L) or in test samples from 43 marathon runners and 24 patients with rhabdomyolysis and highly increased creatine kinase. TnT 2 was increased > 0.2 microgram/L in 5 of 40 patients with renal failure and in 4 of 20 muscular dystrophy patients. The detection limit is 0.012 microgram/L. Day-to-day imprecision (CV) within the range 0.19-14.89 micrograms/L was < 5.8%. In 4955 patients without myocardial damage, 99.6% had TnT < 0.10 microgram/L. Assay comparison (TnT 1 vs TnT 2) over the whole concentration range (i.e., in 323 samples from AMI-suspected patie...

Significant advances in the understanding and management of Duchenne muscular dystrophy (DMD) took place since international guidelines were published in 2010. Our objective was to provide an evidence-based national consensus statement for multidisciplinary care of DMD in Brazil. A combination of the Delphi technique with a systematic review of studies from 2010 to 2016 was employed to classify evidence levels and grade of recommendations. Our recommendations were divided in two parts. We present Part 1 here, where we describe the guideline methodology and overall disease concepts, and also provide recommendations on diagnosis, steroid therapy and new drug treatment perspectives for DMD. The main recommendations: 1) genetic testing in diagnostic suspicious cases should be the first line for diagnostic confirmation; 2) patients diagnosed with DMD should have steroids prescribed; 3) lack of published results for phase 3 clinical trials hinders, for now, the recommendation to use exon skipping or read-through agents. RESUMO Avanços na compreensão e no manejo da distrofia muscular de Duchenne (DMD) ocorreram desde a publicação de diretrizes internacionais em 2010. Nosso objetivo foi elaborar um consenso nacional baseado em evidências de cuidado multidisciplinar dos pacientes com DMD no Brasil. Utilizamos a técnica de Delphi combinada com revisão sistemática da literatura de 2010 a 2016 classificando níveis de evidência e graus de recomendação. Nossas recomendações foram divididas em duas partes. Apresentamos aqui a parte 1, descrevendo a metodologia utilizada e conceitos gerais da doença, e fornecemos recomendações sobre diagnóstico, tratamento com corticosteroides e novas perspectivas de tratamentos medicamentosos. As principais recomendações: 1) testes genéticos deveriam ser a primeira linha para confirmação de casos suspeitos; 2) pacientes com diagnóstico de DMD devem receber corticosteroides; 3) por enquanto, a falta de publicações de resultados dos ensaios clínicos de fase 3, dificulta recomendações de uso medicamentos que "saltam exons" ou "passam" por código de parada prematura.

Biochemical abnormalities have been reported in dystrophin-deficient muscle of boys with Duchenne (severe Xp21) muscular dystrophy or in the murine (mdx) model of the disease. These abnormalities include altered energy metabolism and responses to osmotic shock. In contrast, the situation in brain is less well understood and it is probable that dystrophin is playing a different role (or roles) in this organ. In this study we conclude that the elevation in choline-containing compounds reported in mdx brain is confined to cerebellum and hippocampus in older (> 6 months) mice. We report alterations in glucose metabolism in mdx brain under normal, awake conditions, and a reduced response of brain metabolism to the γ-aminobutyric acidA receptor agonist muscimol. Using brain cortical slices we found no difference in the response of dystrophic tissue to hypoosmotic shock, but increased, substrate-dependent oxygen consumption rates at low oxygen partial pressures.

A traditional knee-ankle-foot orthosis (KAFO) for myopathic patients has been studied for the assessment of loads and fatigue resistance. Starting from this basis a thermoplastic matrix carbon fibre reinforced plastic composite (CFRP) KAFO has been developed in order to reduce the weight. A finite-element simulation programme for deformation analysis was used to compare the behaviour of conventional and CFRP orthosis. There were no breakages either of the prototype or of its parts. The CFRP orthosis allows a weight reduction of more than 40 per cent.

This research focuses on sport practices in the lives of people with “severe” physical dis/abilities. More specifically, this study analyses the commitment to a powerchair hockey career, by both men and women, in order to determine how participation in collective sport practice forms and transforms their life paths. The study is based on a multi-sited ethnography of powerchair hockey in French- and German-speaking Switzerland. Different tools have been used to collect data: participant observation, life narrative interviews, photo-elicitation interviews, and archival research and consultation.
Results show that powerchair hockey is the only team sport organized on a national scale available to powerchair users. A majority of players live with a progressive neuromuscular disease. Powerchair hockey is a social arena located at the intersection of two social worlds: the “able-bodied world” and the “world of dis/ability”. It combines the principles of participation in these two social worlds, thus allowing the insiders and outsiders of these two worlds to meet and form a community.
Commitment to a powerchair hockey career forms and transforms the life paths of people with “severe” physical dis/abilities by providing the conditions for: (1) facilitated movement between the “able-bodied world” and the “world of dis/ability”; (2) the learning of “handicapabilities”; (3) the embodiment of a disposition to mobility; (4) a diversification of spheres of life and networks of interdependence; and (5) joining in a collective history through transmission of a legacy to younger peers. By playing powerchair hockey, athletes distance themselves from the social roles of “disabled people” to which they were assigned prior to a sporting career. At the same time, they perform the social identity of the supercrip athlete. Thus, commitment to sport constitutes a shift away from the life path initially prescribed by doctors and the Swiss Disability Insurance program. Commitment to sport may be considered a form of emancipation from social scripts overdetermined by institutional management of the biological destinies of people living with so-called “severe” physical dis/abilities.

GelScann(1.0) is a user-friendly program that accurately quantitates DNA from CCD imaged agarose gels. The algorithm automatically locates lanes, locates bands within a given lane, and quantitates the intensity of each band. GelScann (1.0) uses a statistical method to discriminate DNA from local background fluorescence. The sensitivity of the LaneFinder and BandFinder can be adjusted by the user interacting with GelScann (1.0)'s option box. We demonstrate that GelScann(1.0) can accurately determine DNA that GelScann(1.0) can accurately determine DNA concentrations for routine molecular biology applications and determine the relative intensities of PCR amplified fragments for genetic testing.

The present study describes the use of simple video games for a 5-week regimen of respiratory muscle training in 15 patients with Duchenne muscular dystrophy (DMD) at various stages of the disease. The games were re-arranged to be operated and driven by the respiratory efforts of the patient and to incorporate accurate ventilation and time measurements. Improvement in respiratory performance was determined by maximum voluntary ventilation (MVV), maximal achieved ventilation (VEmax) during a progressive isocapnic hyperventilation manoeuvre (PIHV) and the PIHV duration. The actual training period was 23 +/- 4 days (mean +/- S.D.) at ventilatory effort of 46 +/- 6% MVV, for 10 +/- 3 min day-1. Patients with moderate impairment of lung function tests (LFT) showed an improvement in MVV, VEmax, and duration of PIHV of 12 +/- 7% (p < 0.02), 53 +/- 25% (p < 0.001) 57 +/- 21% (p < 0.01), respectively. Improvements correlated with actual training time and ventilation level, %MVV, but negatively correlated with years of immobilization and with the initial MVV. We conclude that computerized respiratory games may be applied for breathing exercises and may improve respiratory performance in recently immobilized children with DMD who have moderate impairment of LFT.

Measurements of muscle strength in clinical trials of Duchenne muscular dystrophy have relied heavily on manual muscle testing (MMT). The high level of intra- and interrater variability of MMT compromises clinical study results. We compared the reliability of 12 clinical evaluators in performing MMT and quantitative muscle testing (QMT) on 12 children with muscular dystrophy. QMT was reliable, with an interclass correlation coefficient (ICC) of >0.9 for biceps and grip strength, and >0.8 for quadriceps strength. Training of both subjects and evaluators was easily accomplished. MMT was not as reliable, and required repeated training of evaluators to bring all groups to an ICC >0.75 for shoulder abduction, elbow and hip flexion, knee extension, and ankle dorsiflexion. We conclude that QMT shows greater reliability and is easier to implement than MMT. Consequently, QMT will be a superior measure of strength for use in pediatric, neuromuscular, multicenter clinical trials. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 787–793, 2001.

The amount and distribution of dystrophin protein in myofibers and muscle is highly variable in Becker muscular dystrophy and in exon-skipping trials for Duchenne muscular dystrophy. Here, we investigate a molecular basis for this variability. In muscle from Becker patients sharing the same exon 45-47 in-frame deletion, dystrophin levels negatively correlate with microRNAs predicted to target dystrophin. Seven microRNAs inhibit dystrophin expression in vitro, and three are validated in vivo (miR-146b/miR-374a/miR-31). microRNAs are expressed in dystrophic myofibers and increase with age and disease severity. In exon-skipping-treated mdx mice, microRNAs are significantly higher in muscles with low dystrophin rescue. TNF-α increases microRNA levels in vitro whereas NFκB inhibition blocks this in vitro and in vivo. Collectively, these data show that microRNAs contribute to variable dystrophin levels in muscular dystrophy. Our findings suggest a model where chronic inflammation in distinct microenvironments induces pathological microRNAs, initiating a self-sustaining feedback loop that exacerbates disease progression.

Mutations of the dystrophin DMD gene, essentially deletions of one or several exons, are the cause of two devastating and to date incurable diseases, Duchenne (DMD) and Becker (BMD) muscular dystrophies. Depending upon the preservation or not of the reading frame, dystrophin is completely absent in DMD, or present in either a mutated or a truncated form in BMD. DMD is a severe disease which leads to a premature death of the patients. Therapy approaches are evolving with the aim to transform the severe DMD in the BMD form of the disease by restoring the expression of a mutated or truncated dystrophin. These therapies are based on the assumption that BMD is a mild disease. However, this is not completely true as BMD patients are more or less severely affected and no molecular basis of this heterogeneity of the BMD form of the disease is yet understood. The aim of this review is to report for the correlation between dystrophin structures in BMD deletions in view of this heterogeneity and to emphasize that examining BMD patients in details is highly relevant to anticipate for DMD therapy effects.

In recent years, great advancement has been made in the field of muscular dystrophy. Indeed, molecular biology techniques have allowed the identification of not only the affected gene in Becker (BMD) and Duchenne (DMD) muscular ... From the Laboratoire de ...

Oligonucleotide-based drugs have received considerable attention for their capacity to modulate gene expression very specifically and as a consequence they have found applications in the treatment of many human acquired or genetic diseases. Clinical translation has been often hampered by poor biodistribution, however. Cell-penetrating peptides (CPP) appear as a possibility to increase the cellular delivery of non-permeant biomolecules such as nucleic acids. This review focuses on CPP-delivery of several classes of oligonucleotides (ON), namely antisense oligonucleotides, splice switching oligonucleotides (SSO) and siRNAs. Two main strategies have been used to transport ONs with CPPs: covalent conjugation (which is more appropriate for charge-neutral ON analogues) and non-covalent complexation (which has been used for siRNA delivery essentially). Chemical synthesis, mechanisms of cellular internalization and various applications will be reviewed. A comprehensive coverage of the enorm...