Elastic properties of skeletal muscle and subcutaneous tissues in Duchenne muscular dystrophy by magnetic resonance elastography (MRE): a feasibility study

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Upper Limb Strength and Function Changes during a One-Year Follow-Up in Non-Ambulant Patients with Duchenne Muscular Dystrophy: An Observational Multicenter Trial

International audienceBACKGROUND: Upper limb evaluation of patients with Duchenne Muscular Dystrophy is crucially important to evaluations of efficacy of new treatments in non-ambulant patients. In patients who have lost ambulation, there are few validated and informative outcome measures. In addition, longitudinal data demonstrating sensitivity to clinical evolution of outcome measures over short-term periods are lacking.METHODS: We report here the results of a one-year multicenter study using specifically designed tools to assess grip, pinch strength, and hand function in wheelchair-bound patients. Our study assessed 53 non-ambulant patients with Duchenne muscular dystrophy aged 17.1 ± 4.8 years (range: 9 - 28.1 years). The average Brooke functional score of these patients was 4.6 ± 1.1. The average forced vital capacity was 44.5% predicted and 19 patients used non-invasive ventilation. Patients were assessed at baseline, 6 months, and one year using the Motor Function Measure and innovative devices (namely the MyoSet composed of MyoGrip, MyoPinch, and MoviPlate).RESULTS: Our study confirmed preliminary data previously reported regarding feasibility of use and of reliability of the MyoSet and the correlation at baseline between distal strength and clinical outcomes such as FVC, Brooke score, age, and duration since loss of ambulation. A significant correlation was observed between the distal upper limb strength and clinical variables. The sensitive dynamometers (MyoGrip and MyoPinch) and MoviPlate captured a 12-month change in non-ambulant Duchenne muscular dystrophy patients of all ages.BACKGROUND: ClinicalTrials.gov NCT00993161 NCT00993161

Caractérisation phénotypique et génomique des patients Becker avec délétion des exons 45-55

International audienceLa dystrophie musculaire de Becker (BMD) est une pathologie liée à l’X qui se caractérise par une dégénérescence des muscles squelettiques et/ou associée à une cardiomyopathie. Les patients Becker BMDdel45-55 présentent une délétion “en phase” des exons 45 à 55 dans le gène DMD. Les introns 44 et 55 qui bordent cette délétion contiennent des séquences régulatrices comme des long-non-coding ARN (lncRNA). Chaque patient BMDdel45-55 présente un point de cassure différent et donc un neo-intron unique avec potentiellement des modifications dans les séquences de lncRNA.L’objectif du projet est d’établir une caractérisation génomique d’une cohorte unique de patients BMDdel45-55 et d’étudier des facteurs impliqués dans leur variabilité phénotypique.Nous avons réalisé (i)une caractérisation phénotypique chez 49 patients, (ii)un séquençage du génome entier chez 19/49 patients et (iii)une étude des lncRNA chez 38/49 patients. Nous avons établi le profil des lncRNA dans des myoblastes immortalisés des sujets sains et DMD avec une délétion des exons 45-52 (Myo-45-52).L’étude phénotypique de notre population identifie une cardiomyopathie dilatée (22%), des difficultés à la marche/course (46%), la fatigabilité (34%). Dans 51% l’âge d’apparition des premiers signes est <18 ans (inconnu 22%). L’étude de la présence de lncRNA au niveau génomique met en évidence plusieurs clusters. L’absence génomique de certains lncRNA s’associe avec un phénotype clinique modéré. L’étude des mêmes lncRNA dans les myoblastes immortalisés a permis d’identifier deux lncRNA non-exprimés dans les Myo-45-52.Notre travail présente une caractérisation phénotypique et génomique de la plus grande cohorte de patients BMDdel45-55. Nous avons identifié des clusters avec un phénotype clinique modéré en fonction du nombre génomique de lncRNA. La caractérisation génomique des candidats pour la thérapie par saut d’exons 45-55 serait favorable dans le design des futures essais cliniques thérapeutiques

Phenotypic and genomic characterization of Becker dystrophy patients with 45 to 55 exons deletion

Becker muscular dystrophy (BMD) is an X linked disorder with 1/30000 life births incidence and is characterized by a progressive muscular dystrophy with or without cardiomyopathy. We present a population of 49 BMD patients with a DMD gene in-phase deletion of exons 45 to 55 (BMDdel45-55). Interestingly, emerging regulatory actors as lncRNA are localized in introns 44 and 55 (Bovolenta et al., 2012). Thus, the specific neo-introns of each patient could create or modify the lncRNA and/or RNA non-coding sequences. The objective of this study is to identify modifier factors involved in phenotypic variability in BMDdel45-55 patients. As described in literature, 63% of Duchenne patients are eligible to a multiexon skipping therapy by skipping exons 45 to 55.We performed (i) a phenotypic characterization of 49 patients, (ii) a lncRNA profile in 40/49patients and (iii) a WGS in 19/49patients. We have established the profile of lncRNA presence at genomic level in healthy subjects, muscle biopsies of BMDdel45-55 and DMD patients and human immortalized myoblasts displaying a deletion of 45-52 exons in DMD gene (Myo-45-52).In our cohort 22% of patients have dilatative cardiomyopathy, interestingly in 51% the first signs age was <18 y.o. After the cardiac involvement, the most disabling complains are the walking/running difficulties (46 %) and fatigue (34%). With the exception of one outlier there is a strong correlation between the age of the first signs and the presence of cardiomyopathy. We have established lncRNA profile in 38/49 patients. The cluster with the less numbers of lncRNA have a “milder” phenotype. In addition, in Myo-45-52 the profile of lncRNA expression investigated by RT-PCR, underlined two lacking lncRNA.This study allowed us to describe phenotypic and genomic profile in the largest reported cohort of BMDdel45-55 patients. We identified a cluster with the less numbers of lncRNA with a “milder” phenotype. Genomic data profiling of the candidates for multiexon skipping therapy of 45 to 55 exons would have a favorable contribution in the design of these therapeutic approaches.Bovolenta, M., Erriquez, D., Valli, E., Brioschi, S., Scotton, C., Neri, M., Falzarano, M.S., Gherardi, S., Fabris, M., Rimessi, P., et al. (2012). The DMD locus harbours multiple long non-coding RNAs which orchestrate and control transcription of muscle dystrophin mRNA isoforms. PloS One 7, e45328