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151. Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug

Author

Conklin, Laurie S., primary, Damsker, Jesse M., additional, Hoffman, Eric P., additional, Jusko, William J., additional, Mavroudis, Panteleimon D., additional, Schwartz, Benjamin D., additional, Mengle-Gaw, Laurel J., additional, Smith, Edward C., additional, Mah, Jean K., additional, Guglieri, Michela, additional, Nevo, Yoram, additional, Kuntz, Nancy, additional, McDonald, Craig M., additional, Tulinius, Mar, additional, Ryan, Monique M., additional, Webster, Richard, additional, Castro, Diana, additional, Finkel, Richard S., additional, Smith, Andrea L., additional, Morgenroth, Lauren P., additional, Arrieta, Adrienne, additional, Shimony, Maya, additional, Jaros, Mark, additional, Shale, Phil, additional, McCall, John M., additional, Hathout, Yetrib, additional, Nagaraju, Kanneboyina, additional, van den Anker, John, additional, Ward, Leanne M., additional, Ahmet, Alexandra, additional, Cornish, Michaelyn R., additional, and Clemens, Paula R., additional

Published
2018
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152. Report on the workshop: Meaningful outcome measures for Duchenne muscular dystrophy, London, UK, 30–31 January 2017

Author

Straub, Volker, primary, Mercuri, Eugenio, additional, Aartsma-Rus, Annemieke, additional, Athanasiou, Dimitrios, additional, Balabanov, Pavel, additional, Buccella, Filippo, additional, Caizergues, Didier, additional, Carlier, Pierre, additional, Crossley, Emily, additional, Connolly, Anne M., additional, Duong, Tina, additional, Fischer, Dirk, additional, Furlong, Pat, additional, Goemans, Nathalie, additional, de Groot, Imelda, additional, Guglieri, Michela, additional, Henricson, Erik, additional, Johnson, Alex, additional, Kan, Hermien E., additional, Mayhew, Anna, additional, Mazzone, Elena, additional, McDonald, Craig M., additional, Muntoni, Francesco, additional, Niks, Erik H., additional, Servais, Laurent, additional, Turner, Cathy, additional, Voit, Thomas, additional, Vroom, Elizabeth, additional, and Walter, Glenn, additional

Published
2018
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153. A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy

Author

Goemans, Nathalie, primary, Mercuri, Eugenio, additional, Belousova, Elena, additional, Komaki, Hirofumi, additional, Dubrovsky, Alberto, additional, McDonald, Craig M., additional, Kraus, John E., additional, Lourbakos, Afrodite, additional, Lin, Zhengning, additional, Campion, Giles, additional, Wang, Susanne X., additional, Campbell, Craig, additional, Araujo, A., additional, Bertini, E., additional, Born, P., additional, Cances, C., additional, Chabrol, B., additional, Chae, J.-H., additional, Colomer Oferil, J., additional, Comi, G.P., additional, Cuisset, J.-M., additional, D'Anjou, G., additional, Desguerre, I., additional, Erazo Torricelli, R., additional, Escobar, R., additional, Feder, D., additional, Ferlini, A., additional, Giugliani, R., additional, Henricson, E., additional, Herczegfalvi, A., additional, Jong, Y.-J., additional, Kimura, S., additional, Kirschner, J.-B., additional, Kleinsteuber, K., additional, Kostera-Pruszczyk, A., additional, Kudr, M., additional, Mueller-Felber, W., additional, Niks, E.H., additional, Ogata, K., additional, Palermo, C., additional, Pane, M., additional, Pascual, I., additional, Pereon, Y., additional, Raskin, S., additional, Rasmussen, M., additional, Reed, U., additional, Schara, U., additional, Selby, K., additional, Sobreira, C., additional, Takeshima, Y., additional, Vilchez Padilla, J.J., additional, Vita, G., additional, Vondracek, P., additional, Wiegand, G., additional, and Wilichowski, E., additional

Published
2018
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154. Neurodevelopmental Needs in Young Boys with Duchenne Muscular Dystrophy (DMD): Observations from the Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DNHS).

Author

Thangarajh, Mathula, primary, Spurney, Christopher F., additional, Gordish-Dressman, Heather, additional, Clemens, Paula R., additional, Hoffman, Eric P., additional, McDonald, Craig M., additional, Henricson, Erik K., additional, and Investigators, CINRG, additional

Published
2018
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155. Association Study of Exon Variants in the NF-kappa B and TGF beta Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy

Author

Bello, Luca, Punetha, Jaya, Gordish Dressman, Heather, Giri, Mamta, Hoffman, Eric P, Barp, Andrea, Vianello, Sara, Pegoraro, Elena, Flanigan, Kevin M., Weiss, Robert B., Spitali, Pietro, Aartsma Rus, Annemieke, Straub, Volker, Lochmüller, Hanns, Muntoni, Francesco, Zaharieva, Irina, Ferlini, Alessandra, Mercuri, Eugenio Maria, Tuffery Giraud, Sylvie, Claustres, Mireille, Mcdonald, Craig M., Dunn, Diane M., Swoboda, Kathryn J., Gappmaier, Eduard, Howard, Michael T., Sampson, Jacinda B., Bromberg, Mark B., Butterfield, Russell, Kerr, Lynne, Pestronk, Alan, Florence, Julaine M., Connolly, Anne, Lopate, Glenn, Golumbek, Paul, Schierbecker, Jeanine, Malkus, Betsy, Renna, Renee, Siener, Catherine, Finkel, Richard S., Bonnemann, Carsten G., Medne, Livija, Glanzman, Allan M., Flickinger, Jean, Mendell, Jerry R., King, Wendy M., Lowes, Linda, Alfano, Lindsay, Mathews, Katherine D., Stephan, Carrie, Laubenthal, Karla, Baldwin, Kris, Wong, Brenda, Morehart, Paula, Meyer, Amy, Day, John W., Naughton, Cameron E., Margolis, Marcia, Cnaan, Avital, Abresch, Richard T., Henricson, Erik K., Morgenroth, Lauren P., Duong, Tina, Chidambaranathan, V. Viswanathan, Biggar, W. Douglas, Mcadam, Laura C., Mah, Jean, Tulinius, Mar, Leshner, Robert, Rocha, Carolina Tesi, Thangarajh, Mathula, Kornberg, Andrew, Ryan, Monique, Nevo, Yoram, Dubrovsky, Alberto, Clemens, Paula R., Abdel Hamid, Hoda, Connolly, Anne M., Teasley, Jean, Bertorini, Tulio E., North, Kathryn, Webster, Richard, Kolski, Hanna, Kuntz, Nancy, Driscoll, Sherilyn, Carlo, Jose, Gorni, Ksenija, Lotze, Timothy, Karachunski, Peter, Bodensteiner, John B., Universita degli Studi di Padova, Department of Pediatric Nephrology, Maria Fareri Children's Hospital, Valhalla, New York, New York Medical College (NYMC), Human Genetics, Great Ormond Street Hospital for Children [London] (GOSH), Department of Experimental and Diagnostic Medicine, Section of Medical Genetics, Università degli Studi di Ferrara (UniFE), Università cattolica del Sacro Cuore [Milano] (Unicatt), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Neurology, Newcastle University [Newcastle], Department of Neurosciences [Padova, Italy], University of Padova [Padova, Italy], Massachusetts General Hospital [Boston], King‘s College London, Division of Pediatric Neurology, Cincinnati Children's Hospital Medical Center, Child Development & Exercise Center, Royal Children's Hospital, Washington University in Saint Louis (WUSTL), Institute for Neuromuscular Research, The University of Sydney, Rothamsted Research, University of Alberta, Department of Pediatrics, Feinberg School of Medicine, Northwestern University [Evanston]-Northwestern University [Evanston]-Northwestern University, Stanford School of Medicine [Stanford], Stanford Medicine, and Stanford University-Stanford University

Subjects
0301 basic medicine, Candidate gene, Genetics, Genetics (clinical), Duchenne muscular dystrophy, [SDV]Life Sciences [q-bio], Genome-wide association study, Dystrophin, 0302 clinical medicine, Transforming Growth Factor beta, Osteopontin, Muscular Dystrophy, Muscular dystrophy, Modifier, Child, Exome, biology, NF-kappa B, Exons, Single Nucleotide, Adolescent, European Continental Ancestry Group, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, White People, NO, 03 medical and health sciences, Settore MED/39 - NEUROPSICHIATRIA INFANTILE, Report, medicine, Humans, CD40 Antigens, Polymorphism, Glucocorticoids, Alleles, Case-Control Studies, Genes, Modifier, Genome-Wide Association Study, Latent TGF-beta Binding Proteins, Muscular Dystrophy, Duchenne, Mutation, medicine.disease, Duchenne, 030104 developmental biology, Genes, biology.protein, 030217 neurology & neurosurgery
Abstract

International audience; The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor β [TGFβ]-binding protein 4) have been established as DMD modifiers. We performed a genome-wide association study of age at LoA in a sub-cohort of European or European American ancestry (n = 109) from the Cooperative International Research Group Duchenne Natural History Study (CINRG-DNHS). We focused on protein-altering variants (Exome Chip) and included glucocorticoid treatment as a covariate. As expected, due to the small population size, no SNPs displayed an exome-wide significant p value (< 1.8 × 10-6). Subsequently, we prioritized 438 SNPs in the vicinities of 384 genes implicated in DMD-related pathways, i.e., the nuclear-factor-κB and TGFβ pathways. The minor allele at rs1883832, in the 5'-untranslated region of CD40, was associated with earlier LoA (p = 3.5 × 10-5). This allele diminishes the expression of CD40, a co-stimulatory molecule for T cell polarization. We validated this association in multiple independent DMD cohorts (United Dystrophinopathy Project, Bio-NMD, and Padova, total n = 660), establishing this locus as a DMD modifier. This finding points to cell-mediated immunity as a relevant pathogenetic mechanism and potential therapeutic target in DMD.

Published
2016

156. Treatment effect of idebenone on inspiratory function in patients with Duchenne muscular dystrophy

Author

Buyse, G.M., Voit, Thomas, Schara, Ulrike, Straathof, C.S.M., D’Angelo, M.G., Bernert, G., Cuisset, J.-M., Finkel, Richard S., Goemans, N., Rummey, Christian, Leinonen, Mika, Mayer, Oscar H., Spagnolo, Paolo, Meier, Thomas, McDonald, Craig M., Knipp, F., Van den Hauwe, M., Doppler, V., Gidaro, T., Coopman, S., Lutz, S., Kirschner, J., Borell, S., Will, M., Brighina, E., Gandossini, S., Gorni, K., Falcier, E., Politano, L., D’Ambrosio, P., Taglia, A., Verschuuren, J.J.G.M., Vílchez Padilla, J.J., Muelas Gómez, N., Sejersen, T., Hovmöller, M., Jeannet, P.-Y., Bloetzer, C., Iannaccone, S., Castro, D., Tennekoon, G., Bönnemann, C., Henricson, E., Joyce, N., Apkon, S., Richardson, R.C., and Van den Hauwe, M

Subjects
0301 basic medicine, Male, Ubiquinone, Duchenne muscular dystrophy, Medizin, Pediatrics, Antioxidants, Pulmonary function testing, law.invention, 0302 clinical medicine, Randomized controlled trial, law, respiratory function, Idebenone, Respiratory function, Lung volumes, Muscular Dystrophy, Child, Genetics (clinical), Respiration, Perinatology and Child Health, Inspiratory flow, Pediatrics, Perinatology and Child Health, Pulmonary and Respiratory Medicine, 3. Good health, Respiratory Function Tests, Treatment Outcome, Neurology, Cardiology, Inspiratory Reserve Volume, inspiratory flow, Female, Original Article, medicine.drug, medicine.medical_specialty, Adolescent, Outcomes, Placebo, 03 medical and health sciences, FEV1/FVC ratio, Internal medicine, medicine, Humans, Treatment effect, In patient, business.industry, Original Articles, idebenone, Muscular Dystrophy, Duchenne, Duchenne, medicine.disease, Surgery, 030104 developmental biology, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Assessment of dynamic inspiratory function may provide valuable information about the degree and progression of pulmonary involvement in patients with Duchenne muscular dystrophy (DMD). The aims of this study were to characterize inspiratory function and to assess the efficacy of idebenone on this pulmonary function outcome in a large and well-characterized cohort of 10-18 year-old DMD patients not taking glucocorticoid steroids (GCs) enrolled in the phase 3 randomized controlled DELOS trial. We evaluated the effect of idebenone on the highest flow generated during an inspiratory FVC maneuver (maximum inspiratory flow; V'I,max(FVC)) and the ratio between the largest inspiratory flow during tidal breathing (tidal inspiratory flow; V'I,max(t)) and the V'I,max(FVC). The fraction of the maximum flow that is not used during tidal breathing has been termed inspiratory flow reserve (IFR). DMD patients in both treatment groups of DELOS (idebenone, n = 31; placebo: n = 33) had comparable and abnormally low V'I,max(FVC) at baseline. During the study period, V'I,max(FVC) further declined by -0.29 L/sec in patients on placebo (95%CI: -0.51, -0.08; P = 0.008 at week 52), whereas it remained stable in patients on idebenone (change from baseline to week 52: 0.01 L/sec; 95%CI: -0.22, 0.24; P = 0.950). The between-group difference favoring idebenone was 0.27 L/sec (P = 0.043) at week 26 and 0.30 L/sec (P = 0.061) at week 52. In addition, during the study period, IFR improved by 2.8% in patients receiving idebenone and worsened by -3.0% among patients on placebo (between-group difference 5.8% at week 52; P = 0.040). Although the clinical interpretation of these data is currently limited due to the scarcity of routine clinical practice experience with dynamic inspiratory function outcomes in DMD, these findings from a randomized controlled study nevertheless suggest that idebenone preserved inspiratory muscle function as assessed by V'I,max(FVC) and IFR in patients with DMD. Pediatr Pulmonol. © 2016 The Authors. Pediatric Pulmonology Published by Wiley Periodicals, Inc. ispartof: Pediatric Pulmonology vol:52 issue:4 pages:508-515 ispartof: location:United States status: published

Published
2016

157. Can Quantitative Muscle Strength and Functional Motor Ability Differentiate the Influence of Age and Corticosteroids in Ambulatory Boys with Duchenne Muscular Dystrophy?

Author

Buckon, Cathleen, Sienko, Susan, Bagley, Anita, Sison-Williamson, Mitell, Fowler, Eileen, Staudt, Loretta, Heberer, Kent, McDonald, Craig M., and Sussman, Michael

Subjects
Research Article
Abstract

Background: In the absence of a curative treatment for Duchenne Muscular Dystrophy (DMD), corticosteroid therapy (prednisone, deflazacort) has been adopted as the standard of care, as it slows the progression of muscle weakness and enables longer retention of functional mobility. The ongoing development of novel pharmacological agents that target the genetic defect underlying DMD offer hope for a significant alteration in disease progression; however, substantiation of therapeutic efficacy has proved challenging. Identifying functional outcomes sensitive to the early, subtle changes in muscle function has confounded clinical trials. Additionally, the alterations in disease progression secondary to corticosteroid therapy are not well described making it difficult to ascertain the benefits of novel agents, often taken concurrently with corticosteroids. Objective: The purpose of this study was to examine outcome responsiveness to corticosteroid therapy and age at the onset of a natural history study of ambulatory boys with DMD. Methods: Eighty-five ambulatory boys with DMD (mean age 93 mo, range 49 to 180 mo) were recruited into this study. Fifty participants were on corticosteroid therapy, while 33 were corticosteroid naïve at the baseline assessment. Within each treatment group boys were divided in two age groups, 4 to 7 years and 8 and greater years of age. The Biodex System 3 Pro isokinetic dynamometer was used to assess muscle strength. Motor skills were assessed using the upper two dimensions (standing/walking, running & jumping) of the Gross Motor Function Measure (GMFM 88) and Timed Motor Tests (TMTs) (10-meter run, sit to stand, supine to stand, climb 4-stairs). Two way analysis of variance and Pearson correlations were used for analysis. Results: A main effect for age was seen in select lower extremity muscle groups (hip flexors, knee extensors and ankle dorsiflexors), standing dimension skills, and all TMTs with significantly greater weakness and loss of motor skill ability seen in the older age group regardless of treatment group. Interaction effects were seen for the walking, running, and jumping dimension of the GMFM with the naïve boys scoring higher in the younger group and boys on corticosteroid therapy scoring higher in the older group. The TMT of climb 4-stairs demonstrated a significant treatment effect with the boys on corticosteroid therapy climbing stairs faster than those who were naïve, regardless of age. Examination of individual items within the upper level GMFM dimensions revealed select motor skills are more informative of disease progression than others; indicating their potential to be sensitive indicators of alterations in disease progression and intervention efficacy. Analysis of the relationship between muscle group strength and motor skill performance revealed differences in use patterns in the corticosteroid versus naïve boys. Conclusion: Significant muscle weakness is apparent in young boys with DMD regardless of corticosteroid treatment; however, older boys on corticosteroid therapy tend to have greater retention of muscle strength and motor skill ability than those who are naive. Quantification of muscle strength via isokinetic dynamometry is feasible and sensitive to the variable rates of disease progression in lower extremity muscle groups, but possibly most informative are the subtle changes in the performance characteristics of select motor skills. Further analysis of longitudinal data from this study will explore the influence of corticosteroid therapy on muscle strength and further clarify its impact on motor performance.

Published
2016

158. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Author

McDonald, Craig M, primary, Campbell, Craig, additional, Torricelli, Ricardo Erazo, additional, Finkel, Richard S, additional, Flanigan, Kevin M, additional, Goemans, Nathalie, additional, Heydemann, Peter, additional, Kaminska, Anna, additional, Kirschner, Janbernd, additional, Muntoni, Francesco, additional, Osorio, Andrés Nascimento, additional, Schara, Ulrike, additional, Sejersen, Thomas, additional, Shieh, Perry B, additional, Sweeney, H Lee, additional, Topaloglu, Haluk, additional, Tulinius, Már, additional, Vilchez, Juan J, additional, Voit, Thomas, additional, Wong, Brenda, additional, Elfring, Gary, additional, Kroger, Hans, additional, Luo, Xiaohui, additional, McIntosh, Joseph, additional, Ong, Tuyen, additional, Riebling, Peter, additional, Souza, Marcio, additional, Spiegel, Robert J, additional, Peltz, Stuart W, additional, Mercuri, Eugenio, additional, Alfano, Lindsay N, additional, Eagle, Michelle, additional, James, Meredith K, additional, Lowes, Linda, additional, Mayhew, Anna, additional, Mazzone, Elena S, additional, Nelson, Leslie, additional, Rose, Kristy J, additional, Abdel-Hamid, Hoda Z, additional, Apkon, Susan D, additional, Barohn, Richard J, additional, Bertini, Enrico, additional, Bloetzer, Clemens, additional, de Vaud, Lausanne Canton, additional, Butterfield, Russell J, additional, Chabrol, Brigitte, additional, Chae, Jong-Hee, additional, Jongno-gu, Daehak-ro, additional, Comi, Giacomi Pietro, additional, Darras, Basil T, additional, Dastgir, Jahannaz, additional, Desguerre, Isabelle, additional, Escobar, Raul G, additional, Finanger, Erika, additional, Guglieri, Michela, additional, Hughes, Imelda, additional, Iannaccone, Susan T, additional, Jones, Kristi J, additional, Karachunski, Peter, additional, Kudr, Martin, additional, Lotze, Timothy, additional, Mah, Jean K, additional, Mathews, Katherine, additional, Nevo, Yoram, additional, Parsons, Julie, additional, Péréon, Yann, additional, de Queiroz Campos Araujo, Alexandra Prufer, additional, Renfroe, J Ben, additional, de Resende, Maria Bernadete Dutra, additional, Ryan, Monique, additional, Selby, Kathryn, additional, Tennekoon, Gihan, additional, and Vita, Giuseppe, additional

Published
2017
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159. Pulmonary Endpoints in Duchenne Muscular Dystrophy. A Workshop Summary

Author

Finder, Jonathan, primary, Mayer, Oscar Henry, additional, Sheehan, Daniel, additional, Sawnani, Hemant, additional, Abresch, R. Ted, additional, Benditt, Joshua, additional, Birnkrant, David J., additional, Duong, Tina, additional, Henricson, Erik, additional, Kinnett, Kathi, additional, McDonald, Craig M., additional, and Connolly, Anne M., additional

Published
2017
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161. Developing standardized corticosteroid treatment for Duchenne muscular dystrophy

Author

Guglieri, Michela, primary, Bushby, Kate, additional, McDermott, Michael P., additional, Hart, Kimberly A., additional, Tawil, Rabi, additional, Martens, William B., additional, Herr, Barbara E., additional, McColl, Elaine, additional, Wilkinson, Jennifer, additional, Kirschner, Janbernd, additional, King, Wendy M., additional, Eagle, Michele, additional, Brown, Mary W., additional, Willis, Tracey, additional, Hirtz, Deborah, additional, Shieh, Perry B., additional, Straub, Volker, additional, Childs, Anne-Marie, additional, Ciafaloni, Emma, additional, Butterfield, Russell J., additional, Horrocks, Iain, additional, Spinty, Stefan, additional, Flanigan, Kevin M., additional, Kuntz, Nancy L., additional, Baranello, Giovanni, additional, Roper, Helen, additional, Morrison, Leslie, additional, Mah, Jean K., additional, Manzur, Adnan Y., additional, McDonald, Craig M., additional, Schara, Ulrike, additional, von der Hagen, Maja, additional, Barohn, Richard J., additional, Campbell, Craig, additional, Darras, Basil T., additional, Finkel, Richard S., additional, Vita, Giuseppe, additional, Hughes, Imelda, additional, Mongini, Tiziana, additional, Pegoraro, Elena, additional, Wicklund, Matthew, additional, Wilichowski, Ekkehard, additional, Bryan Burnette, W., additional, Howard, James F., additional, McMillan, Hugh J., additional, Thangarajh, Mathula, additional, and Griggs, Robert C., additional

Published
2017
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165. Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy

Author

Campbell, Craig, Barohn, Richard J, Bertini, Enrico, Chabrol, Brigitte, Comi, Giacomo Pietro, Darras, Basil T, Finkel, Richard S, Flanigan, Kevin M, Goemans, Nathalie, Iannaccone, Susan T, Jones, Kristi J, Kirschner, Janbernd, Mah, Jean K, Mathews, Katherine D, McDonald, Craig M, Mercuri, Eugenio, Nevo, Yoram, Péréon, Yann, Renfroe, J Ben, Ryan, Monique M, Sampson, Jacinda B, Schara, Ulrike, Sejersen, Thomas, Selby, Kathryn, Tulinius, Már, Vílchez, Juan J, Voit, Thomas, Wei, Lee-Jen, Wong, Brenda L, Elfring, Gary, Souza, Marcio, McIntosh, Joseph, Trifillis, Panayiota, Peltz, Stuart W, and Muntoni, Francesco

Abstract

Aim:Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Materials & methods:Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] ≥300–<400 or <400 m). Meta-analyses examined 6MWD change from baseline to week 48. Results:Statistically significant differences in 6MWD change with ataluren versus placebo were observed across all three meta-analyses. Least-squares mean difference (95% CI): ITT (n = 342), +17.2 (0.2–34.1) m, p = 0.0473; ≥300–<400 m (n = 143), +43.9 (18.2–69.6) m, p = 0.0008; <400 m (n = 216), +27.7 (6.4–49.0) m, p = 0.0109. Conclusion:These meta-analyses support previous evidence for ataluren in slowing disease progression versus placebo in patients with nmDMD over 48 weeks. Treatment benefit was most evident in patients with a baseline 6MWD ≥300–<400 m (the ambulatory transition phase), thereby informing future trial design.

Published
2020
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166. Safety and effectiveness of ataluren: comparison of results from the STRIDE Registry and CINRG DMD Natural History Study

Author

Mercuri, Eugenio, Muntoni, Francesco, Osorio, Andrés Nascimento, Tulinius, Már, Buccella, Filippo, Morgenroth, Lauren P, Gordish-Dressman, Heather, Jiang, Joel, Trifillis, Panayiota, Zhu, Jin, Kristensen, Allan, Santos, Claudio L, Henricson, Erik K, McDonald, Craig M, and Desguerre, Isabelle

Abstract

Aim:Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, multicenter registry providing real-world evidence regarding ataluren use in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). We examined the effectiveness of ataluren + standard of care (SoC) in the registry versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS), DMD genotype–phenotype/–ataluren benefit correlations and ataluren safety. Patients & methods:Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established disease progression predictors (registry cut-off date, 9 July 2018). Results & conclusion:Kaplan–Meier analyses demonstrated that ataluren + SoC significantly delayed age at loss of ambulation and age at worsening performance in timed function tests versus SoC alone (p ≤ 0.05). There were no DMD genotype–phenotype/ataluren benefit correlations. Ataluren was well tolerated. These results indicate that ataluren + SoC delays functional milestones of DMD progression in patients with nmDMD in routine clinical practice. ClinicalTrials.gov identifier:NCT02369731. ClinicalTrials.gov identifier:NCT02369731.

Published
2020
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167. Towards regulatory endorsement of drug development tools to promote the application of model-informed drug development in Duchenne muscular dystrophy.

Author

Conrado, Daniela J., Larkindale, Jane, Berg, Alexander, Hill, Micki, Burton, Jackson, Abrams, Keith R., Abresch, Richard T., Bronson, Abby, Chapman, Douglass, Crowther, Michael, Duong, Tina, Gordish-Dressman, Heather, Harnisch, Lutz, Henricson, Erik, Kim, Sarah, McDonald, Craig M., Schmidt, Stephan, Vong, Camille, Wang, Xiaoxing, and Wong, Brenda L.

Abstract

Drug development for rare diseases is challenged by small populations and limited data. This makes development of clinical trial protocols difficult and contributes to the uncertainty around whether or not a potential therapy is efficacious. The use of data standards to aggregate data from multiple sources, and the use of such integrated databases to develop statistical models can inform protocol development and reduce the risks in developing new therapies. Achieving regulatory endorsement of such models through defined pathways at the US Food and Drug Administration and European Medicines Authority allows such tools to be used by the drug development community for defined contexts of use without further need for discussion of the underlying model(s). The Duchenne Regulatory Science Consortium (D-RSC) has brought together multiple stakeholders to develop a clinical trial simulation tool for Duchenne muscular dystrophy using such an approach. Here we describe the work of D-RSC as an example of how such an approach may be effective at reducing uncertainty in drug development for rare diseases, and thus bringing effective therapies to patients faster. [ABSTRACT FROM AUTHOR]

Published
2019
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168. Twice‐weekly glucocorticosteroids in infants and young boys with Duchenne muscular dystrophy.

Author

Connolly, Anne M., Zaidman, Craig M., Golumbek, Paul T., Cradock, Mary M., Flanigan, Kevin M., Kuntz, Nancy L., Finkel, Richard S., McDonald, Craig M., Iannaccone, Susan T., Anand, Pallavi, Siener, Catherine A., Florence, Julaine M., Lowes, Linda P., Alfano, Lindsay N., Johnson, Linda B., Nicorici, Alina, Nelson, Leslie L., and Mendell, Jerry R.

Abstract

Introduction: Glucocorticosteroids (GC) are effective in slowing weakness in boys with Duchenne muscular dystrophy (DMD). Methods: This is a multisite, 1‐year, open‐label trial of twice‐weekly prednisolone (5 mg/kg/dose) in infants/young boys (0.4–2.4 years) with DMD. We compared changes in Bayley III Scales of Infant Development (Bayley‐III) with untreated boys followed for 1 year (historical control cohort [HCC]). Twenty‐three of 25 participants completed the study. Results: Treated boys gained an average of 0.5 points on the Bayley‐III gross motor scaled score (GMSS) compared with the HCC who, on average, declined 1.3 points (P = 0.03). All boys maintained linear growth, and none developed Cushingoid features. Excessive weight gain occurred in 13 of 23 (56%) boys. Discussion: This study provides evidence that twice‐weekly GC is well tolerated in infants and young boys with DMD and improves GMSS. Excessive weight gain is a potential risk. Longer follow‐up is required to determine whether early GC initiation is feasible in most infants/boys with DMD. Muscle Nerve 59:650–657, 2019 See editorial on pages 638–639 in this issue. [ABSTRACT FROM AUTHOR]

Published
2019
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169. DMD genotypes and loss of ambulation in the CINRG Duchenne Natural History Study

Author

Bello, Luca, Morgenroth, Lauren P., Gordish-Dressman, Heather, Hoffman, Eric P., McDonald, Craig M., Cirak, Sebahattin, Bello, Luca, Morgenroth, Lauren P., Gordish-Dressman, Heather, Hoffman, Eric P., McDonald, Craig M., and Cirak, Sebahattin

Abstract

Objective:To correlate time to loss of ambulation (LoA) and different truncating DMD gene mutations in a large, prospective natural history study of Duchenne muscular dystrophy (DMD), with particular attention to mutations amenable to emerging molecular treatments.Methods:We analyzed data from the Cooperative International Neuromuscular Research Group Duchenne Natural History Study for participants with DMD single- or multi-exon deletions or duplications with defined exon boundaries (n = 186), or small mutations identified by sequencing (n = 26, including 16 nonsense point mutations). We performed a time-to-event analysis of LoA, a strong indicator of overall disease severity, adjusting for glucocorticoid treatment and genetic modifiers.Results:Participants with deletions amenable to skipping of exon 44 had later LoA (median 14.8 years, hazard ratio 0.31, 95% confidence interval 0.14-0.69, p = 0.004). Age at LoA did not differ significantly in participants with deletions amenable to exon 45, 51, and 53 skipping, duplications, and small rearrangements. Nonsense mutation DMD also showed a typical median age at LoA (11.1 years), with a few outliers (ambulatory around or after 16 years of age) carrying stop codons within in-frame exons, more often situated in the rod domain.Conclusions:As exon 44 skipping-amenable DMD has a later LoA, mutation-specific randomization and selection of placebo groups are essential for the success of clinical trials.

Published
2016

170. Neuromuscular Disease Management and Rehabilitation, Part II: Specialty Care and Therapeutics, an Issue of Physical Medicine and Rehabilitation Clinics,

Author

Joyce, Nanette C., McDonald, Craig M., Joyce, Nanette C., and McDonald, Craig M.

Subjects
Rehabilitation--Methodology, Medical rehabilitation, Neuromuscular manifestations of general diseases, Neuromuscular diseases--Patients--Rehabilitation, Rehabilitation
Abstract

Neuromuscular disease is a broad term that encompasses many diseases and ailments that either directly or indirectly impair the function of the body's muscle system, via the nerves. This issue of PMR will provide an overview of current treatments and therapies for a variety of diseases. The GEs have gone through every issue published since 1998, and these 23 chapters will be meant to fill the numerous gaps in PMR's coverage of the field over the past decade. The issue will include chapters on different treatment techniques, such as exercises, stretches, and nutrition. It will also provide chapters focusing on specific areas of the body, specific conditions, and an update on mobility technology for those with NMDs.

Published
2012

171. Association Study of Exon Variants in the NF-κB and TGFβ Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy

Author

Bello, Luca, primary, Flanigan, Kevin M., additional, Weiss, Robert B., additional, Spitali, Pietro, additional, Aartsma-Rus, Annemieke, additional, Muntoni, Francesco, additional, Zaharieva, Irina, additional, Ferlini, Alessandra, additional, Mercuri, Eugenio, additional, Tuffery-Giraud, Sylvie, additional, Claustres, Mireille, additional, Straub, Volker, additional, Lochmüller, Hanns, additional, Barp, Andrea, additional, Vianello, Sara, additional, Pegoraro, Elena, additional, Punetha, Jaya, additional, Gordish-Dressman, Heather, additional, Giri, Mamta, additional, McDonald, Craig M., additional, Hoffman, Eric P., additional, Dunn, Diane M., additional, Swoboda, Kathryn J., additional, Gappmaier, Eduard, additional, Howard, Michael T., additional, Sampson, Jacinda B., additional, Bromberg, Mark B., additional, Butterfield, Russell, additional, Kerr, Lynne, additional, Pestronk, Alan, additional, Florence, Julaine M., additional, Connolly, Anne, additional, Lopate, Glenn, additional, Golumbek, Paul, additional, Schierbecker, Jeanine, additional, Malkus, Betsy, additional, Renna, Renee, additional, Siener, Catherine, additional, Finkel, Richard S., additional, Bonnemann, Carsten G., additional, Medne, Livija, additional, Glanzman, Allan M., additional, Flickinger, Jean, additional, Mendell, Jerry R., additional, King, Wendy M., additional, Lowes, Linda, additional, Alfano, Lindsay, additional, Mathews, Katherine D., additional, Stephan, Carrie, additional, Laubenthal, Karla, additional, Baldwin, Kris, additional, Wong, Brenda, additional, Morehart, Paula, additional, Meyer, Amy, additional, Day, John W., additional, Naughton, Cameron E., additional, Margolis, Marcia, additional, Cnaan, Avital, additional, Abresch, Richard T., additional, Henricson, Erik K., additional, Morgenroth, Lauren P., additional, Duong, Tina, additional, Chidambaranathan, V. Viswanathan, additional, Biggar, W. Douglas, additional, McAdam, Laura C., additional, Mah, Jean, additional, Tulinius, Mar, additional, Leshner, Robert, additional, Rocha, Carolina Tesi, additional, Thangarajh, Mathula, additional, Kornberg, Andrew, additional, Ryan, Monique, additional, Nevo, Yoram, additional, Dubrovsky, Alberto, additional, Clemens, Paula R., additional, Abdel-Hamid, Hoda, additional, Connolly, Anne M., additional, Teasley, Jean, additional, Bertorini, Tulio E., additional, North, Kathryn, additional, Webster, Richard, additional, Kolski, Hanna, additional, Kuntz, Nancy, additional, Driscoll, Sherilyn, additional, Carlo, Jose, additional, Gorni, Ksenija, additional, Lotze, Timothy, additional, Karachunski, Peter, additional, and Bodensteiner, John B., additional

Published
2016
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172. Idebenone reduces respiratory complications in patients with Duchenne muscular dystrophy

Author

McDonald, Craig M., primary, Meier, Thomas, additional, Voit, Thomas, additional, Schara, Ulrike, additional, Straathof, Chiara S.M., additional, D'Angelo, M. Grazia, additional, Bernert, Günther, additional, Cuisset, Jean-Marie, additional, Finkel, Richard S., additional, Goemans, Nathalie, additional, Rummey, Christian, additional, Leinonen, Mika, additional, Spagnolo, Paolo, additional, Buyse, Gunnar M., additional, Bernert, G., additional, Knipp, F., additional, Buyse, G.M., additional, Goemans, N., additional, van den Hauwe, M., additional, Voit, T., additional, Doppler, V., additional, Gidaro, T., additional, Cuisset, J.-M., additional, Coopman, S., additional, Schara, U., additional, Lutz, S., additional, Kirschner, J., additional, Borell, S., additional, Will, M., additional, D'Angelo, M.G., additional, Brighina, E., additional, Gandossini, S., additional, Gorni, K., additional, Falcier, E., additional, Politano, L., additional, D'Ambrosio, P., additional, Taglia, A., additional, Verschuuren, J.J.G.M., additional, Straathof, C.S.M., additional, Vílchez Padilla, J.J., additional, Muelas Gómez, N., additional, Sejersen, T., additional, Hovmöller, M., additional, Jeannet, P.-Y., additional, Bloetzer, C., additional, Iannaccone, S., additional, Castro, D., additional, Tennekoon, G., additional, Finkel, R., additional, Bönnemann, C., additional, McDonald, C., additional, Henricson, E., additional, Joyce, N., additional, Apkon, S., additional, and Richardson, R.C., additional

Published
2016
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177. The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study

Author

McDonald, Craig M, Henricson, Erik K, Abresch, R Ted, Florence, Julaine M, Eagle, Michelle, Gappmaier, Eduard, Glanzman, Allan M, PTC124-GD-007-DMD Study Group, Spiegel, Robert, Barth, Jay, Elfring, Gary, Reha, Allen, Peltz, Stuart, and Schara, Ulrike (Beitragende*r)

Subjects
Male, Supine position, Time Factors, Outcome Assessment, Physiology, PTC124-GD-007-DMD Study Group, Duchenne muscular dystrophy, Medizin, Observation, Walking, Medical and Health Sciences, chemistry.chemical_compound, timed function tests, Clinical endpoint, Muscular Dystrophy, Longitudinal Studies, Child, Pediatric, Oxadiazoles, 6-minute walk test, Hand Strength, ambulation, natural history, Predictive value of tests, 6.1 Pharmaceuticals, myometry, Ambulatory, Duchenne/ Becker Muscular Dystrophy, medicine.medical_specialty, Adolescent, Intellectual and Developmental Disabilities (IDD), Clinical Trials and Supportive Activities, Placebo, Cellular and Molecular Neuroscience, Rare Diseases, Double-Blind Method, Clinical Research, Predictive Value of Tests, Physiology (medical), Hand strength, medicine, Humans, Preschool, Glucocorticoids, Neurology & Neurosurgery, business.industry, Electromyography, Evaluation of treatments and therapeutic interventions, medicine.disease, Duchenne, Ataluren, Brain Disorders, Health Care, chemistry, prediction of loss of function, Physical therapy, Exercise Test, Neurology (clinical), dystrophinopathy, business
Abstract

Introduction: Duchenne muscular dystrophy (DMD) subjects ≥5 years with nonsense mutations were followed for 48 weeks in a multicenter, randomized, double-blind, placebo-controlled trial of ataluren. Placebo arm data (N = 57) provided insight into the natural history of the 6-minute walk test (6MWT) and other endpoints. Methods: Evaluations performed every 6 weeks included the 6-minute walk distance (6MWD), timed function tests (TFTs), and quantitative strength using hand-held myometry. Results: Baseline age (≥7 years), 6MWD, and selected TFT performance are strong predictors of decline in ambulation (Δ6MWD) and time to 10% worsening in 6MWD. A baseline 6MWD of

Published
2013

178. The 6-minute walk test and other clinical endpoints in duchenne muscular dystrophy: reliability, concurrent validity, and minimal clinically important differences from a multicenter study

Author

McDonald, Craig M, Henricson, Erik K, Abresch, R Ted, Florence, Julaine, Eagle, Michelle, Gappmaier, Eduard, Glanzman, Allan M, PTC124-GD-007-DMD Study Group, Spiegel, Robert, Barth, Jay, Elfring, Gary, Reha, Allen, Peltz, Stuart W, and Schara, Ulrike (Beitragende*r)

Subjects
Duchenne muscular dystrophy, muscular dystrophy, Male, medicine.medical_specialty, Time Factors, Outcome Assessment, Physiology, PTC124-GD-007-DMD Study Group, Concurrent validity, Medizin, Context (language use), Walking, Medical and Health Sciences, Cellular and Molecular Neuroscience, PedsQL, Physical medicine and rehabilitation, Heart Rate, Physiology (medical), Outcome Assessment, Health Care, medicine, Clinical endpoint, Humans, Muscular dystrophy, timed function test, Oxadiazoles, Neurology & Neurosurgery, 6-minute walk test, business.industry, Minimal clinically important difference, ambulation, Main Articles, Reproducibility of Results, medicine.disease, Duchenne, humanities, Clinical trial, Health Care, Muscular Dystrophy, Duchenne, natural history, myometry, Ambulatory, Physical therapy, energy expenditure index, Disease Progression, Exercise Test, Neurology (clinical), business
Abstract

Introduction: An international clinical trial enrolled 174 ambulatory males ≥5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pretreatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCIDs) of the 6-minute walk test (6MWT) and other endpoints. Methods: Screening and baseline evaluations included the 6-minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL, heart rate–determined energy expenditure index, and other exploratory endpoints. Results: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. Conclusions: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression. Muscle Nerve 48: 357–368, 2013

Published
2013

179. Deflazacort versus prednisone/prednisolone for maintaining motor function and delaying loss of ambulation: A post HOC analysis from the ACT DMD trial.

Author

Shieh, Perry B., Mcintosh, Joseph, Jin, Fengbin, Souza, Marcio, Elfring, Gary, Narayanan, Siva, Trifillis, Panayiota, Peltz, Stuart W., Mcdonald, Craig M., Darras, Basil T., AND THE ACT DMD STUDY GROUP, and THE ACT DMD STUDY GROUP

Abstract

Introduction: ACT DMD was a 48-week trial of ataluren for nonsense mutation Duchenne muscular dystrophy (nmDMD). Patients received corticosteroids for ≥6 months at entry and stable regimens throughout study. This post hoc analysis compares efficacy and safety for deflazacort and prednisone/prednisolone in the placebo arm.Methods: Patients received deflazacort (n = 53) or prednisone/prednisolone (n = 61). Endpoints included change from baseline in 6-minute walk distance (6MWD), timed function tests, estimated age at loss of ambulation (extrapolated from 6MWD).Results: Mean changes in 6MWD were -39.0 m (deflazacort; 95% confidence limit [CL], -68.85, -9.17) and -70.6 m (prednisone/prednisolone; 95% CL, -97.16, -44.02). Mean changes in 4-stair climb were 3.79 s (deflazacort; 95% CL, 1.54, 6.03) and 6.67 s (prednisone/prednisolone; 95% CL, 4.69, 8.64).Conclusions: This analysis, limited by its post hoc nature, suggests greater preservation of 6MWD and 4-stair climb with deflazacort vs. prednisone/prednisolone. A head-to-head comparison will better define these differences. Muscle Nerve 58: 639-645, 2018. [ABSTRACT FROM AUTHOR]

Published
2018
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180. Placebo‐controlled Phase 2 Trial of Drisapersen for Duchenne Muscular Dystrophy.

Author

McDonald, Craig M., Wong, Brenda, Flanigan, Kevin M., Wilson, Rosamund, de Kimpe, Sjef, Lourbakos, Afrodite, Lin, Zhengning, Campion, Giles, and the DEMAND V study group

Subjects
*PLACEBOS, *TREATMENT of Duchenne muscular dystrophy, *PHARMACOKINETICS, *PULMONARY function tests, *DRUG efficacy
Abstract

Abstract: Objective: This double‐blind, randomized, placebo‐controlled Phase 2 study (NCT01462292) assessed the 24‐week efficacy, safety, tolerability, and pharmacokinetics of two different subcutaneous drisapersen doses, and the 24‐week off‐dose persistent effect, in ambulant Duchenne muscular dystrophy (DMD) patients. Methods: Male DMD patients (≥5 years; time to rise from floor ≤15 s) were randomized to drisapersen 3 mg/kg/week, 6 mg/kg/week or placebo. The primary efficacy endpoint was change from baseline in 6‐minute walking distance (6MWD) at week 24. Secondary endpoints included changes in timed function tests, muscle strength, and pulmonary function tests. Results: Fifty‐one patients were randomized to placebo (N = 16), drisapersen 3 mg/kg/week (N = 17) or 6 mg/kg/week (N = 18). All but 2 patients had baseline rise from floor time <7 s. This study was exploratory and not prospectively powered; however, a difference in mean 6MWD versus placebo in favor of drisapersen 6 mg/kg/week was observed at week 24 (27.1 m; P = 0.069) and maintained 24 weeks off‐treatment (27.9 m; P = 0.177). The 3 mg/kg/week group showed no statistically significant difference in mean 6MWD versus placebo. For some secondary endpoints, a more positive response in favor of drisapersen 6 mg/kg/week compared to placebo was shown. Drisapersen had a long half‐life with steady state reached after approximately 36 weeks. Most common adverse events in both drisapersen groups were related to injection site reactions and subclinical proteinuria. Interpretation: Drisapersen 6 mg/kg/week for 24 weeks resulted in a treatment benefit in 6MWD, largely maintained 24 weeks off‐treatment. This study provided insights for further studies to optimize dosage regimen. [ABSTRACT FROM AUTHOR]

Published
2018
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181. Mexiletine for muscle cramps in amyotrophic lateral sclerosis: A randomized, double-blind crossover trial.

Author

Oskarsson, Björn, Moore, Dan, Mozaffar, Tahseen, Ravits, John, Wiedau‐Pazos, Martina, Parziale, Nicholas, Joyce, Nanette C., Mandeville, Ross, Goyal, Namita, Cudkowicz, Merit E., Weiss, Michael, Miller, Robert G., McDonald, Craig M., and Wiedau-Pazos, Martina

Abstract

Introduction: More than 90% of amyotrophic lateral sclerosis (ALS) patients have muscle cramps, but evidence-based treatments have not been available.Methods: A multicenter, double-blind, placebo-controlled crossover trial of mexiletine 150 mg twice daily was conducted in ALS patients requesting treatment of symptomatic muscle cramps.Results: Muscle cramp frequency was reduced in 18 of 20 patients; 13 reductions were attributed to treatment (P < 0.05). The average reduction, based on t tests, was 1.8 cramps per day (a reduction from 5.3 with placebo to 3.5 with mexiletine). The estimated reduction of cramp severity was 15 units on a 100-unit scale (P = 0.01) from a baseline average of 46. No effect on fasciculations was noted. One patient discontinued the study because of dizziness, and another patient discontinued the study to start open-label mexiletine therapy. No serious adverse event occurred.Discussion: Mexiletine is a well tolerated and effective medication for controlling the symptom of muscle cramps in ALS. Muscle Nerve, 2018. [ABSTRACT FROM AUTHOR]

Published
2018
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182. A multinational study on motor function in early-onset FSHD.

Author

Mah, Jean K., Jia Feng, Jacobs, Marni B., Duong, Tina, Carroll, Kate, de Valle, Katy, Carty, Cara L., Morgenroth, Lauren P., Guglieri, Michela, Ryan, Monique M., Clemens, Paula R., Thangarajh, Mathula, Webster, Richard, Smith, Edward, Connolly, Anne M., McDonald, Craig M., Karachunski, Peter, Tulinius, Mar, Harper, Amy, and Cnaan, Avital

Published
2018
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183. Longitudinal community walking activity in Duchenne muscular dystrophy.

Author

Fowler, Eileen G., Staudt, Loretta A., Heberer, Kent R., Sienko, Susan E., Buckon, Cathleen E., Bagley, Anita M., Sussman, Michael D., and McDonald, Craig M.

Subjects
COMPARATIVE studies, DUCHENNE muscular dystrophy, GAIT in humans, RESEARCH methodology, MEDICAL cooperation, RESEARCH, WALKING, EVALUATION research, DISEASE progression
Abstract

Introduction: Natural history studies for Duchenne muscular dystrophy (DMD) have not included measures of community ambulation.Methods: Step activity (SA) monitors quantified community ambulation in 42 boys (ages 4-16 years) with DMD with serial enrollment up to 5 years by using a repeated-measures mixed model. Additionally, data were compared with 10-meter walk/run (10mWR) speed to determine validity and sensitivity.Results: There were significant declines in average strides/day and percent strides at moderate, high and pediatric high rates as a function of age (P < 0.05). Significant correlations for 10mWR versus high and low stride rates were found at baseline (P < 0.05). SA outcomes were sensitive to change over 1 year, but the direction and parameter differed by age group (younger vs. older). Changes in strides/day and percentages of high frequency and low frequency strides correlated significantly with changes in 10mWR speed (P < 0.05).Discussion: Community ambulation data provide valid and sensitive real-world measures that may inform clinical trials. Muscle Nerve 57: 401-406, 2018. [ABSTRACT FROM AUTHOR]

Published
2018
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184. A presynaptic congenital myasthenic syndrome attributed to a homozygous sequence variant in <italic>LAMA5</italic>.

Author

Maselli, Ricardo A., Arredondo, Juan, Vázquez, Jessica, Chong, Jessica X., Bamshad, Michael J., Nickerson, Deborah A., Lara, Marian, Ng, Fiona, Lo, Victoria Lee, Pytel, Peter, and McDonald, Craig M.

Subjects
MYASTHENIA gravis, CLINICAL trials, NEUROMUSCULAR transmission, LAMININS, COGNITIVE ability, ELECTRON microscopy
Abstract

Abstract: We report a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin α5 subunit gene (LAMA5). The variant c.8046C > T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had normal cognitive function, but magnetic resonance brain imaging showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation at 2 Hz showed 50% decrement of compound muscle action potential amplitudes but 250% facilitation immediately after exercise, similar to that seen in Lambert–Eaton myasthenic syndrome. Endplate studies demonstrated a profound reduction of the endplate potential quantal content but normal amplitudes of miniature endplate potentials. Electron microscopy showed endplates with increased postsynaptic folding that were denuded or only partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin α5 to SV2A and impaired laminin‐521 cell adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding α‐laminins. [ABSTRACT FROM AUTHOR]

Published
2018
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185. Eteplirsen Treatment Attenuates Respiratory Decline in Ambulatory and Non-Ambulatory Patients with Duchenne Muscular Dystrophy

Author

Khan, Navid, Eliopoulos, Helen, Han, Lixin, Kinane, T. Bernard, Lowes, Linda P., Mendell, Jerry R., Gordish-Dressman, Heather, Henricson, Erik K., and McDonald, Craig M.

Abstract

Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years. Evaluate the effects of eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls. Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and <18 years were included for all patients; mixed-model analyses characterized FVC% p annual change. FVC% p annual change was greater for CINRG DNHS Exon 51 controls (– 6.00) versus patients in studies 201/202, study 204, and study 301 (– 2.19, P < 0.001; – 3.66, P0.004; and – 3.79, P0.017, respectively). FVC% p annual change in all eteplirsen studies suggested treatment benefit compared with the Genotyped CINRG DNHS (– 5.67) and All CINRG DNHS (– 5.56) cohorts (P < 0.05, all comparisons). Significant, clinically meaningful attenuation of FVC%p decline was observed in eteplirsen-treated patients versus CINRG DNHS controls.

Published
2019
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186. THE ROLE OF THE NEUROMUSCULAR MEDICINE SPECIALIST AND PHYSIATRY IN THE MANAGEMENT OF NEUROMUSCULAR DISEASE

Author

McDonald, Craig M. and Fowler, William M.

Subjects
Patient Care Team, Neuromuscular Diseases, Neuropsychological Tests, Article, Spinal Curvatures, Respiratory Function Tests, Radiography, Disability Evaluation, Heart Function Tests, Exercise Test, Humans, Muscle Strength, Range of Motion, Articular, Muscle, Skeletal
Abstract

The neuromuscular medicine, and physiatry specialists are key health care providers who work cooperatively with a multidisciplinary team to provide coordinated care for persons with Neuromuscular diseases (NMDs). The director or coordinator of the team must be aware of the potential issues specific to NMDs and be able to access the interventions that are the foundations for proper care in NMD. These include health maintenance and proper monitoring of disease progression and complications to provide anticipatory, preventive care and optimum management. Ultimate goals include maximizing health and functional capacities, performing medical monitoring and surveillance to inhibit and prevent complications, and promoting access and full integration into the community in order to optimize quality of life.

Published
2012

188. Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial

Author

Buyse, Gunnar M, primary, Voit, Thomas, additional, Schara, Ulrike, additional, Straathof, Chiara S M, additional, D'Angelo, M Grazia, additional, Bernert, Günther, additional, Cuisset, Jean-Marie, additional, Finkel, Richard S, additional, Goemans, Nathalie, additional, McDonald, Craig M, additional, Rummey, Christian, additional, and Meier, Thomas, additional

Published
2015
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192. Presynaptic congenital myasthenic syndrome with a homozygous sequence variant in LAMA5 combines myopia, facial tics, and failure of neuromuscular transmission.

Author

Maselli, Ricardo A., Arredondo, Juan, Vázquez, Jessica, Chong, Jessica X., Bamshad, Michael J., Nickerson, Deborah A., Lara, Marian, Ng, Fiona, Lo, Victoria L., Pytel, Peter, and McDonald, Craig M.

Abstract

Defects in genes encoding the isoforms of the laminin alpha subunit have been linked to various phenotypic manifestations, including brain malformations, muscular dystrophy, ocular defects, cardiomyopathy, and skin abnormalities. We report here a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin alpha-5 subunit gene ( LAMA5). The variant c.8046C>T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had muscle weakness, myopia, and facial tics. Magnetic resonance imaging of brain showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation revealed 50% decrement of compound muscle action potential amplitudes and 250% facilitation immediately after exercise, Endplate studies identified a profound reduction of the endplate potential quantal content and endplates with normal postsynaptic folding that were denuded or partially occupied by small nerve terminals. Expression studies revealed that p.Arg2659Trp caused decreased binding of laminin alpha-5 to SV2A and impaired laminin-521 cell-adhesion and cell projection support in primary neuronal cultures. In summary, this report describing severe neuromuscular transmission failure in a patient with a LAMA5 mutation expands the list of phenotypes associated with defects in genes encoding alpha-laminins. [ABSTRACT FROM AUTHOR]

Published
2017
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194. One Year Outcome of Boys With Duchenne Muscular Dystrophy Using the Bayley-III Scales of Infant and Toddler Development

Author

Connolly, Anne M., primary, Florence, Julaine M., additional, Cradock, Mary M., additional, Eagle, Michelle, additional, Flanigan, Kevin M., additional, McDonald, Craig M., additional, Karachunski, Peter I., additional, Darras, Basil T., additional, Bushby, Kate, additional, Malkus, Elizabeth C., additional, Golumbek, Paul T., additional, Zaidman, Craig M., additional, Miller, J. Philip, additional, and Mendell, Jerry R., additional

Published
2014
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195. Motor and cognitive assessment of infants and young boys with Duchenne Muscular Dystrophy: results from the Muscular Dystrophy Association DMD Clinical Research Network

Author

Connolly, Anne M., primary, Florence, Julaine M., additional, Cradock, Mary M., additional, Malkus, Elizabeth C., additional, Schierbecker, Jeanine R., additional, Siener, Catherine A., additional, Wulf, Charlie O., additional, Anand, Pallavi, additional, Golumbek, Paul T., additional, Zaidman, Craig M., additional, Philip Miller, J., additional, Lowes, Linda P., additional, Alfano, Lindsay N., additional, Viollet-Callendret, Laurence, additional, Flanigan, Kevin M., additional, Mendell, Jerry R., additional, McDonald, Craig M., additional, Goude, Erica, additional, Johnson, Linda, additional, Nicorici, Alina, additional, Karachunski, Peter I., additional, Day, John W., additional, Dalton, Joline C., additional, Farber, Janey M., additional, Buser, Karen K., additional, Darras, Basil T., additional, Kang, Peter B., additional, Riley, Susan O., additional, Shriber, Elizabeth, additional, Parad, Rebecca, additional, Bushby, Kate, additional, and Eagle, Michelle, additional

Published
2013
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197. A Randomized, Double-Blind Trial of Lisinopril and Losartan for the Treatment of Cardiomyopathy in Duchenne Muscular Dystrophy

Author

Allen, Hugh D., primary, Flanigan, Kevin M, additional, Thrush, Philip T., additional, Dvorchik, Igor, additional, Yin, Han, additional, Canter, Charles, additional, Connolly, Anne M., additional, Parrish, Mark, additional, McDonald, Craig M., additional, Braunlin, Elizabeth, additional, Colan, Steven D., additional, Day, John, additional, Darras, Basil, additional, and Mendell, Jerry R., additional

Published
2013
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199. Metabolic syndrome in adolescents with spinal cord dysfunction.

Author

Nelson, Mindy Dopler, Nelson, Mindy Dopler, Widman, Lana M, Abresch, Richard Ted, Stanhope, Kimber, Havel, Peter J, Styne, Dennis M, McDonald, Craig M, Nelson, Mindy Dopler, Nelson, Mindy Dopler, Widman, Lana M, Abresch, Richard Ted, Stanhope, Kimber, Havel, Peter J, Styne, Dennis M, and McDonald, Craig M

Abstract

ObjectiveThe purpose of this study was to determine the prevalence of components of the metabolic syndrome in adolescents with spinal cord injury (SCI) and spina bifida (SB), and their associations with obesity in subjects with and without SCI and SB.MethodsFifty-four subjects (20 SCI and 34 SB) age 11 to 20 years with mobility impairments from lower extremity paraparesis were recruited from a hospital-based clinic. Sixty able-bodied subjects who were oversampled for obesity served as controls (CTRL). Subjects were categorized as obese if their percent trunk fat measured by dual x-ray absorptiometry (DXA) was > 30.0% for males and > 35.0% for females. Ten SCI, 24 SB, and 19 CTRL subjects were classified as obese. Fasting serum samples were collected to determine serum glucose, insulin, and lipid concentrations. Metabolic syndrome was defined as having > or =3 of the following components: (a) obesity; (b) high-density lipoprotein (HDL) <45 mg/dL for males; <50 mg/dL for females; (c) triglycerides 2100 mg/dL; (d) systolic or diastolic blood pressure > or =95th percentile for age/ height/gender, and (e) insulin resistance determined by either fasting serum glucose 100-125 mg/dL; fasting insulin > or =20 microU /mL; or homeostasis model assessment of insulin resistance > or = 4.0.ResultsMetabolic syndrome was identified in 32.4% of the SB group and 55% of the SCI group. Metabolic syndrome occurred at a significantly higher frequency in obese subjects (SB = 45.8%, SCI = 100%, CTRL = 63.2%) than nonobese subjects (SB = 0%, SCI = 10%, CTRL = 2.4%).ConclusionsThe prevalence of metabolic syndrome in adolescents with SB/SCI is quite high, particularly in obese individuals. These findings have important implications due to the known risks of cardiovascular diseases and diabetes mellitus associated with metabolic syndrome in adults, particularly those with spinal cord dysfunction.

Published
2007

200. Clinical trial readiness in non-ambulatory boys and men with duchenne muscular dystrophy: MDA-DMD network follow-up.

Author

Connolly, Anne M., Florence, Julaine M., Zaidman, Craig M., Golumbek, Paul T., Mendell, Jerry R., Flanigan, Kevin M., Karachunski, Peter I., Day, John W., McDonald, Craig M., Darras, Basil T., Kang, Peter B., Siener, Catherine A., Gadeken, Rebecca K., Anand, Pallavi, Schierbecker, Jeanine R., Malkus, Elizabeth C., Lowes, Linda P., Alfano, Lindsay N., Johnson, Linda, and Nicorici, Alina

Subjects
ADRENOCORTICAL hormones, HORMONE therapy, DIAGNOSIS of Duchenne muscular dystrophy, DUCHENNE muscular dystrophy, GRIP strength, RANGE of motion of joints, LONGITUDINAL method, RESEARCH funding, RESPIRATORY measurements, PATIENT participation, SYMPTOMS
Abstract

Introduction: Outcomes sensitive to change over time in non-ambulatory boys/men with Duchenne muscular dystrophy (DMD) are not well-established.Methods: Subjects (n = 91; 16.8 ± 4.5 years old) were assessed at baseline and 6-month intervals for 2 years. We analyzed all subjects using an intent-to-treat model and a subset of stronger subjects with Brooke Scale score ≤4, using repeated measures.Results: Eight patients (12-33 years old) died during the study. Sixty-six completed 12-month follow-up, and 51 completed 24-month follow-up. Those taking corticosteroids performed better at baseline, but rates of decline were similar. Forced vital capacity percent predicted (FVC% predicted) declined significantly only after 2 years. However, Brooke and Egen Klassifikation (EK) Scale scores, elbow flexion, and grip strength declined significantly over both 1 and 2 years.Conclusion: Brooke and EK Scale scores, elbow flexion, and grip strength were outcomes most responsive to change. FVC% predicted was responsive to change over 2 years. Corticosteroids benefited non-ambulatory DMD subjects but did not affect decline rates of measures tested here. Muscle Nerve 54: 681-689, 2016. [ABSTRACT FROM AUTHOR]

Published
2016
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