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      Long Term Natural History Data in Ambulant Boys with Duchenne Muscular Dystrophy: 36-Month Changes

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      1 , 1 , 1 , 2 , 3 , 4 , 4 , 3 , 1 , 5 , 6 , 7 , 8 , 8 , 3 , 9 , 10 , 11 , 1 , 1 , 12 , 1 ,   6 , 1 , 14 , 13 , 13 , 14 , 14 , 12 , 11 , 9 , 10 , 15 , 7 , 8 , 6 , 4 , 1 , *
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          Abstract

          The 6 minute walk test has been recently chosen as the primary outcome measure in international multicenter clinical trials in Duchenne muscular dystrophy ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment, age and 6 minute walk test values at baseline. Ninety-six patients from 11 centers were assessed at baseline and 12, 24 and 36 months after baseline using the 6 minute walk test and the North Star Ambulatory Assessment. Three boys (3%) lost the ability to perform the 6 minute walk test within 12 months, another 13 between 12 and 24 months (14%) and 11 between 24 and 36 months (12%). The 6 minute walk test showed an average overall decline of −15.8 (SD 77.3) m at 12 months, of −58.9 (SD 125.7) m at 24 months and −104.22 (SD 146.2) m at 36 months. The changes were significantly different in the two baseline age groups and according to the baseline 6 minute walk test values (below and above 350 m) (p<0.001). The changes were also significantly different according to steroid treatment (p = 0.01). Similar findings were found for the North Star Ambulatory Assessment. These are the first 36 month longitudinal data using the 6 minute walk test and North Star Ambulatory Assessment in Duchenne muscular dystrophy. Our findings will help not only to have a better idea of the progression of the disorder but also provide reference data that can be used to compare with the results of the long term extension studies that are becoming available.

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          Most cited references5

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          LTBP4 genotype predicts age of ambulatory loss in Duchenne muscular dystrophy.

          Duchenne muscular dystrophy (DMD) displays a clinical range that is not fully explained by the primary DMD mutations. Ltbp4, encoding latent transforming growth factor-β binding protein 4, was previously discovered in a genome-wide scan as a modifier of murine muscular dystrophy. We sought to determine whether LTBP4 genotype influenced DMD severity in a large patient cohort. We analyzed nonsynonymous single nucleotide polymorphisms (SNPs) from human LTBP4 in 254 nonambulatory subjects with known DMD mutations. These SNPs, V194I, T787A, T820A, and T1140M, form the VTTT and IAAM LTBP4 haplotypes. Individuals homozygous for the IAAM LTBP4 haplotype remained ambulatory significantly longer than those heterozygous or homozygous for the VTTT haplotype. Glucocorticoid-treated patients who were IAAM homozygotes lost ambulation at 12.5 ± 3.3 years compared to 10.7 ± 2.1 years for treated VTTT heterozygotes or homozygotes. IAAM fibroblasts exposed to transforming growth factor (TGF) β displayed reduced phospho-SMAD signaling compared to VTTT fibroblasts, consistent with LTBP4' role as a regulator of TGFβ. LTBP4 haplotype influences age at loss of ambulation, and should be considered in the management of DMD patients. Copyright © 2013 American Neurological Association.
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            SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy.

            Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient-patient variability in disease onset and progression and response to glucocorticoids is seen, suggesting genetic or environmental modifiers. Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied. Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%-19% less grip strength (CINRG cohort p = 0.0003). Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects.
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              North Star Ambulatory Assessment, 6-minute walk test and timed items in ambulant boys with Duchenne muscular dystrophy.

              The North Star Ambulatory Assessment is a functional scale specifically designed for ambulant boys affected by Duchenne muscular dystrophy (DMD). Recently the 6-minute walk test has also been used as an outcome measure in trials in DMD. The aim of our study was to assess a large cohort of ambulant boys affected by DMD using both North Star Assessment and 6-minute walk test. More specifically, we wished to establish the spectrum of findings for each measure and their correlation. This is a prospective multicentric study involving 10 centers. The cohort included 112 ambulant DMD boys of age ranging between 4.10 and 17 years (mean 8.18±2.3 DS). Ninety-one of the 112 were on steroids: 37/91 on intermittent and 54/91 on daily regimen. The scores on the North Star assessment ranged from 6/34 to 34/34. The distance on the 6-minute walk test ranged from 127 to 560.6 m. The time to walk 10 m was between 3 and 15 s. The time to rise from the floor ranged from 1 to 27.5 s. Some patients were unable to rise from the floor. As expected the results changed with age and were overall better in children treated with daily steroids. The North Star assessment had a moderate to good correlation with 6-minute walk test and with timed rising from floor but less with 10 m timed walk/run test. The 6-minute walk test in contrast had better correlation with 10 m timed walk/run test than with timed rising from floor. These findings suggest that a combination of these outcome measures can be effectively used in ambulant DMD boys and will provide information on different aspects of motor function, that may not be captured using a single measure. Copyright © 2010. Published by Elsevier B.V.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                1 October 2014
                : 9
                : 10
                : e108205
                Affiliations
                [1 ]Department of Paediatric Neurology, Catholic University, Rome, Italy
                [2 ]Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy
                [3 ]Department of Neurosciences, Psychiatry and Anaesthesiology, University of Messina, Messina, Italy
                [4 ]Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, Rome, Italy
                [5 ]Child Neurology and Psychiatry Unit, “Casimiro Mondino” Foundation, Pavia, Italy
                [6 ]Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
                [7 ]Neuromuscular Disease Unit, Giannina Gaslini Institute, Genoa, Italy
                [8 ]Dipartimento di Medicina Sperimentale, Seconda Università di Napoli, Napoli, Italy
                [9 ]Department of Developmental Neuroscience, Stella Maris Institute, Pisa, Italy
                [10 ]Department of Neurosciences, University of Padua, Padua, Italy
                [11 ]Child Neurology and Psychiatry Unit, Maggiore Hospital, Bologna, Italy
                [12 ]Neuromuscular Center, San Giovanni Battista Hospital, University of Turin, Turin, Italy
                [13 ]Metabolic and Neuromuscular Unit, Meyer Hospital, Florence, Italy
                [14 ]Developmental Neurology Unit, Neurological Institute Carlo Besta, Milan, Italy
                [15 ]Department of Neurology, San Raffaele Scientific Institute, Milan, Italy
                The Hospital for Sick Children, Canada
                Author notes

                Competing Interests: Dr. Pane, Dr. Sivo and E. Mazzone report no disclosures. Dr. Sormani: serves on a scientific advisory board for Biogen Idec.; has received funding for travel or speaker honoraria from Merck Serono; serves as consultant for Merck Serono, Actelion Pharmaceuticals Lts. Biogen Idec, and Synthon; and serves on the speakers' bureaus of Teva Pharmaceutical Industries Ltd., Merck Serono, and Biogen Idec. Dr. D'Amico and Dr. Messina report no disclosures. Dr. Vita serves as an Associate Editor for Neurological Sciences. L. Fanelli, Dr. Berardinelli, Dr. Torrente, V. Lanzillotta, Dr. Viggiano, Dr. D'Ambrosio, F. Cavallaro, S. Frosini, Dr. Barp, Dr. Bonfiglio, Dr. Scalise, R. De Sanctis, E. Rolle, Dr. Graziano, Dr. Magri, Dr. Palermo, F. Rossi, Dr. Donati, Dr. Sacchini, Dr. Arnoldi, Dr. Baranello report no disclosures. Dr. Mongini has served on a scientific advisory board for Telethon Italy; has received funding for travel from Genzyme Corporation; and has received research support from AIFA (Italian Government Drug Agency) and Telethon Italy. Dr. Pini, Dr. Battini report no disclosures. Dr. Pegoraro has served on a scientific advisory board for BioMarin Pharmaceutical Inc.; has received funding for travel from Genzyme Corporation; and has received speaker honoraria from MedaPharma; and receives research support from Wellstone and Telethon Italy. Dr. Previtali, Dr. Bruno, Dr. Politano report no disclosures. Dr. Comi: is site PI for the PTC extension study of Ataluren in DMD, for the GSK study on exon skipping; receives research support from Telethon Italy and SMA Europe. Dr. Bertini is site PI for the PTC extension study of Ataluren in DMD, for the GSK study on exon skipping. He also receives funds from the Italian Telethon, the Italian Ministry of Health and SMA Europe for observational studies on outcome measures. Dr. Mercuri is site PI for the PTC extension study of Ataluren in DMD, for the GSK Prosensa and Sarepta studies on exon skipping. He also receives funds from the Italian Telethon and SMA Europe. He has acted as advisory board for Acceleron Pharma, Shire and PTC Therapeutics, Inc, Prosensa. The disclosures shown in the paper do not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: MP ESM SS LF RDS EM. Performed the experiments: SM LF RDS VL FC ER SF MTA FR. Analyzed the data: MP ESM SS MPS SM AD AC GV AB YT VL EV PD FC SF AB SB CP RS RDS ER AG FM MAD MS MTA FR GB TM AP RB EP SP CB LP GPC EB EM. Wrote the paper: MP ESM SS MPS SM AD AC GV LF AB YT VL EV PD FC SF AB SB CP RS RDS ER AG FM MAD MS MTA FR GB TM AP RB EP SP CB LP GPC EB EM.

                Article
                PONE-D-14-17572
                10.1371/journal.pone.0108205
                4182715
                25271887
                080a86a3-85e3-4207-b7e7-3cba7232f39a
                Copyright @ 2014

                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.

                History
                : 18 April 2014
                : 18 August 2014
                Page count
                Pages: 6
                Funding
                The study was funded by two Telethon UILDM grants (Italy) (GUP 09010 and GUP 07009). Dr. Mazzone is a Telethon funded TREAT NMD fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Genetics
                Heredity
                Genetic Linkage
                Sex Linkage
                X-Linked Traits
                Duchenne Muscular Dystrophy
                Medicine and Health Sciences
                Clinical Genetics
                Clinical Medicine
                Clinical Trials
                Neurology
                Muscular Dystrophies
                Neuromuscular Diseases
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Individual data is available on request, database shared with the Italian Telethon funder of the study. Please contact eumercuri@ 123456gmail.com .

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