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Dogan C.,Neuromuscular Reference Center | De Antonio M.,Neuromuscular Reference Center | De Antonio M.,University of Paris Descartes | Hamroun D.,Montpellier University Hospital Center | And 46 more authors.
PLoS ONE | Year: 2016

Background Myotonic Dystrophy type 1 (DM1) is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity. Methods We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18y) from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Téléthon DM1 survey (n =970), and morbidity and mortality using the French National Health Service Database (n =3301). Results Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate. Conclusion Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials. © 2016 Dogan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Seferian A.M.,Institute of Myology | Moraux A.,Institute of Myology | Annoussamy M.,Institute of Myology | Canal A.,Institute of Myology | And 22 more authors.
PLoS ONE | Year: 2015

Introduction: 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. Patients and 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 noninvasive ventilation. Patients were assessed at baseline, 6 months, and one year using the Motor Function Measure and innovative devices (namely the MyoSet composed of Myo- Grip, 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. Trial Registration: ClinicalTrials.gov NCT00993161 NCT00993161. © 2015 Seferian et al.


Voermans N.C.,Radboud University Nijmegen | Benveniste O.,University Pierre and Marie Curie | Minnema M.C.,University Utrecht | Lokhorst H.,University Utrecht | And 16 more authors.
Neurology | Year: 2014

Objective: Sporadic late-onset nemaline myopathy (SLONM) is a rare, late-onset myopathy that progresses subacutely. If associated with a monoclonal gammopathy of unknown significance (MGUS), the outcome is unfavorable: the majority of these patients die within 1 to 5 years of respiratory failure. This study aims to qualitatively assess the long-term treatment effect of high-dose melphalan (HDM) followed by autologous stem cell transplantation (SCT) in a series of 8 patients with SLONM-MGUS. Methods: We performed a retrospective case series study (n = 8) on the long-term (1-8 years) treatment effect of HDM followed by autologous SCT (HDM-SCT) on survival, muscle strength, and functional capacities. Results: Seven patients showed a lasting moderate-good clinical response, 2 of them after the second HDM-SCT. All of them had a complete, a very good partial, or a partial hematologic response. One patient showed no clinical or hematologic response and died. Conclusions: This case series shows the positive effect of HDM-SCT in this rare disorder. Factors that may portend an unfavorable outcome are a long disease course before the hematologic treatment and a poor hematologic response. Age at onset, level and type of M protein (k vs l), and severity of muscle weakness were not associated with a specific outcome. Classification of evidence: This study provides Class IV evidence that for patients with SLONMMGUS, HDM-SCT increases the probability of survival and functional improvement. ©2014 American Academy of Neurology.


Bouchard J.-P.,Enfant Jesus Hospital | Cossette L.,Laval University | Bassez G.,Neuromuscular Reference Center | Bassez G.,French Institute of Health and Medical Research | Puymirat J.,Laval University
Journal of Neurology | Year: 2014

Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy in adult. The aim of this study was to investigate the natural history of skeletal muscle weakness in adults, in a cross-sectional, retrospective study. In a cohort of 204 adult DM1 patients, we quantified muscle impairment, handgrip force and physical disability. Muscle strength was similarly affected in the legs and in the arms, the right and left side, and distally more than proximally in patients. The earliest and the most affected skeletal muscles were the digit flexors, foot dorsiflexors and neck flexors; whereas the elbow and knee extensors and flexors were the least affected muscle groups. The rate of decline of the muscle strength was −0.111 units/year. The handgrip values were lower in DM1 patients than the normative values and the rate of decline in handgrip force per year was −0.24 kg. Limitation in mobility or walking is observed in 84 % of DM1 patients but requirement of wheelchair is infrequent (3 %). The decrease in muscle strength, handgrip force and the increase in physical disability were highly correlated with duration of the disease and the number of CTG repeats in the blood. Significant association was found between decline in muscle strength and the age at onset, physical disability and the age of patients at evaluation, handgrip force and gender. Decline in muscle weakness is very slow and although limitation when walking is a common manifestation of DM1 in patients, the requirement of wheelchair is infrequent. © 2014, Springer-Verlag Berlin Heidelberg.


Servais L.,Groupe hospitalier La Pitie Salpetriere | Deconinck N.,Neuromuscular Reference Center | Moraux A.,Groupe hospitalier La Pitie Salpetriere | Benali M.,Genethon | And 15 more authors.
Neuromuscular Disorders | Year: 2013

Upper limb assessment in non-ambulant patients remains a challenge. We have designed new tools to precisely assess pinch (MyoPinch), grip (MyoGrip), wrist flexion and extension (MyoWrist) strength. We have also designed a new tool to assess the ability of patients to produce repetitive flexion/extension movements of wrist and fingers (MoviPlate). We have assessed the feasibility and reliability of these new tools in 30 non-ambulant patients with Duchenne muscular dystrophy and in 30 age-matched male controls. Existing measures, such as Motor Function Measure, Tapping, and the Brooke Upper Extremity Functional Rating Scale were also performed. Results demonstrated that assessments were feasible in nearly all upper limbs tested for MyoGrip, MyoPinch and MoviPlate. The reliability of all tests, including MyoWrist which was not feasible in the patients presenting with contractures, was excellent in patients as in controls. Motor capacities decrease with the number of months spent in the wheelchair. The scores in the tests were partially correlated with each other, and with clinical measures such as vital capacity, Motor Function Measure, functional hand scale and Brooke score. This study validates a panel of upper limb muscle strength and function measures for Duchenne Muscular Dystrophy which can be applied from controls to extremely weak patients. © 2012 Elsevier B.V.


PubMed | Montpellier University Hospital Center, CNRS Biometry and Evolutionary Biology Laboratory, Hospices civils de Lyon and Neuromuscular Reference Center
Type: | Journal: Annals of physical and rehabilitation medicine | Year: 2016

To assess the applicability and the responsiveness of the motor function measure 1 (MFM) in the myotonic dystrophy type 1 (DM1) population.We conducted an observational, retrospective, multicenter cohort study using data from the MFM database (http://www.motor-function-measure.org/data-bank.aspx). Only DM1 patients with at least one MFM-32 score were included. The distributions of the MFM scores (total score and 3 subscores) were analyzed by age. MFM responsiveness was estimated in patients with at least two MFMs (at least six months between the two evaluations). Hypothetical sample sizes for specific effect sizes in clinical trial scenarios are given.The descriptive study includes 618 patients from 29 physical medicine and rehabilitation or neurology department aged 6.2-80.4 years. 1038 MFM-32 for DM1 patients are registered in the MFM database and 228 patients have a least two evaluations. 930 MFM were realized in adults patients (>18years old). Mean age at the MFM execution was: MFM D1 subscore (standing and transfers) is the more sensitive score to show deterioration (-2.32 points/year). MFM D2 (proximal and axial motricity) and D3 (distal motricity) subscores showed less changes over time (-1.43+-4.25 points/year for D2, -0.53+-4.18 points/year for D3). Significant responsiveness was obtained with the D1 subscore (standardized response mean [SRM]=.550).MFM scale and particularly the D1 subscore is a reliable and valid outcome measure applicable in longitudinal follow-up and clinical trials in the DM1 population.


PubMed | PMSI Division, Human Genetic Research Unit, Bordeaux University Hospital Center, Neuromuscular Reference Center and 14 more.
Type: Journal Article | Journal: PloS one | Year: 2016

Myotonic Dystrophy type 1 (DM1) is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity.We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18 y) from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Tlthon DM1 survey (n = 970), and morbidity and mortality using the French National Health Service Database (n = 3301).Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate.Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials.


CAMBRIDGE, Mass.--(BUSINESS WIRE)--Eli Lilly and Company, one of the top 15 global pharmaceutical companies, has joined the Collaborative Trajectory Analysis Project (cTAP), a unique partnership of many stakeholders all committed to accelerating scientific discovery and bringing new treatments to Duchenne Muscular Dystrophy (DMD) patients more rapidly. “Lilly is proud to support the efforts of cTAP, which is making a real difference in our understanding of the progression of DMD, and how variations across patients make it particularly difficult to design effective clinical trials,” said Kraig Kinchen, M.D., senior medical director of Lilly’s Bio-medicines Core Team. “cTAP is a model that brings together the collective talent of a multi-stakeholder community. We all share a common interest in speeding the development of potentially effective therapies for Duchenne patients and their families.” Debra Miller, founder and CEO of CureDuchenne, a leading advocacy group in the fight against Duchenne, said: “Advancing our scientific knowledge of Duchenne and the way in which its progression varies across patients is cTAP’s mission. CureDuchenne was the founding advocacy group supporting cTAP and we are thrilled by Lilly’s contribution.” “By sharing trial data, Lilly is showing real leadership,” added Pat Furlong, founding president and CEO of Parent Project Muscular Dystrophy. “PPMD has a long history with Lilly and their tadalafil trial, and we believe the data collected from our community will be valuable to the mission of cTAP.” Duchenne Muscular Dystrophy is a progressive, fatal disease of boys characterized by gradual weakening of muscles. It is the most common fatal genetic disorder diagnosed in childhood. Most Duchenne patients die in their 20s. Though a Phase III human clinical trial of tadalafil, a phosphodiesterase inhibitor, in Duchenne ultimately failed to meet its targets for proving efficacy in slowing the decline in patients’ ability to walk, the data generated by the trial are essential to expanding scientific understanding of the rate of decline in boys with Duchenne. cTAP has characterized the variable rates at which Duchenne patients that exhibit similar symptoms often progress. This variation makes it difficult to design clinical drug trials that can definitively prove the efficacy of new treatments. Because Duchenne is a rare disease, with only about 20,000 new cases worldwide each year, it is virtually impossible to conduct large-scale trials with many patients, an approach that can be used to overcome variability in more prevalent disorders. “Through our collaboration with cTAP we have been able to create new models that eliminate much of the statistical variation we see in patients in clinical trials of experimental Duchenne treatments,” said Professor Nathalie Goemans, head of the Neuromuscular Reference Center for Children at the University Hospitals in Leuven, Belgium. “With these new data from Lilly, we will be able to assess how well our predictive tools – developed using natural history data – perform in the placebo arm of a clinical trial for a Duchenne treatment. That’s why Lilly’s participation is so critically important.” The Collaborative Trajectory Analysis Project, or cTAP, is a novel group enabling leading clinical experts to solve the most urgent problems in Duchenne drug development. cTAP is a dynamic alliance of scientists, drug companies, patient advocacy organizations, and registries and clinical centers in DMD across Europe and the U.S. The collaboration also brings leaders in biostatistical outcomes research to the fight against Duchenne. cTAP is curating and growing what is already the largest natural history database of DMD. This enables it to develop near-term solutions for some of the key problems in designing clinical trials and analyzing their results. To learn more, please visit ctap-duchenne.org. Duchenne Muscular Dystrophy is a uniformly fatal, progressive, muscle-wasting disease affecting about one in 3,500-6,000 male live births. Patients with Duchenne lack the ability to make dystrophin, a protein crucial to muscle function. As their muscles deteriorate, they progressively lose the ability to walk, feed themselves, turn over in bed, and ultimately to breathe. While there is no cure, the past decade has seen an explosion in research, resulting in more than 15 therapies entering clinical development, with some receiving limited approval. Learn more about Duchenne at cureduchenne.org and parentprojectmd.org.

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