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1. Defining clinical endpoints in limb girdle muscular dystrophy: a GRASP-LGMD study.

Author

Doody, Amy, Alfano, Lindsay, Diaz-Manera, Jordi, Lowes, Linda, Mozaffar, Tahseen, Mathews, Katherine, Weihl, Conrad, Wicklund, Matthew, Hung, Man, Statland, Jeffrey, and Johnson, Nicholas

Subjects
Clinical outcome assessments, Clinical trials, Limb girdle muscular dystrophy, Muscular dystrophy, Therapeutic development, Humans, Muscular Dystrophies, Limb-Girdle, Phenotype, Muscle, Skeletal, Mutation, Sarcoglycanopathies, Nerve Tissue Proteins, Molecular Chaperones, HSP40 Heat-Shock Proteins, Pentosyltransferases, Anoctamins
Abstract

BACKGROUND: The Limb Girdle Muscular Dystrophies (LGMDs) are characterized by progressive weakness of the shoulder and hip girdle muscles as a result of over 30 different genetic mutations. This study is designed to develop clinical outcome assessments across the group of disorders. METHODS/DESIGN: The primary goal of this study is to evaluate the utility of a set of outcome measures on a wide range of LGMD phenotypes and ability levels to determine if it would be possible to use similar outcomes between individuals with different phenotypes. We will perform a multi-center, 12-month study of 188 LGMD patients within the established Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) Research Consortium, which is comprised of 11 sites in the United States and 2 sites in Europe. Enrolled patients will be clinically affected and have mutations in CAPN3 (LGMDR1), ANO5 (LGMDR12), DYSF (LGMDR2), DNAJB6 (LGMDD1), SGCA (LGMDR3), SGCB (LGMDR4), SGCD (LGMDR6), or SGCG (LGMDR5, or FKRP-related (LGMDR9). DISCUSSION: To the best of our knowledge, this will be the largest consortium organized to prospectively validate clinical outcome assessments (COAs) in LGMD at its completion. These assessments will help clinical trial readiness by identifying reliable, valid, and responsive outcome measures as well as providing data driven clinical trial decision making for future clinical trials on therapeutic agents for LGMD. The results of this study will permit more efficient clinical trial design. All relevant data will be made available for investigators or companies involved in LGMD therapeutic development upon conclusion of this study as applicable. TRIAL REGISTRATION: Clinicaltrials.gov NCT03981289; Date of registration: 6/10/2019.

Published
2024

2. Correction to: A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot–Marie–Tooth type 1A

Author

Attarian, Shahram, Young, Peter, Brannagan, Thomas H., Adams, David, Van Damme, Philip, Thomas, Florian P., Casanovas, Carlos, Kafaie, Jafar, Tard, Céline, Walter, Maggie C., Péréon, Yann, Walk, David, Stino, Amro, de Visser, Marianne, Verhamme, Camiel, Amato, Anthony, Carter, Gregory, Magy, Laurent, Statland, Jeffrey M., and Felice, Kevin

Published
2024
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3. Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis

Author

Benatar, Michael, Granit, Volkan, Statland, Jeffrey M., Heckmann, Jeannine M., McMillan, Corey T., Elman, Lauren, Ravits, John, Katz, Jonathan, Trivedi, Jaya, Swenson, Andrea, Burns, Ted M., Caress, James, Jackson, Carlayne, Maiser, Samuel, Pioro, Erik P., So, Yuen, Macklin, Eric A., Malaspina, Andrea, Rogers, Mary-Louise, Hornstein, Eran, Lombardi, Vittoria, Renfrey, Danielle, Shepheard, Stephanie, Magen, Iddo, Cohen, Yahel, Rademakers, Rosa, McHutchison, Caroline A., Petrucelli, Leonard, and Wuu, Joanne

Published
2024
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4. Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy.

Author

Statland, Jeffrey, Campbell, Craig, Desai, Urvi, Karam, Chafic, Díaz-Manera, Jordi, Guptill, Jeffrey, Korngut, Lawrence, Genge, Angela, Tawil, Rabi, Elman, Lauren, Joyce, Nanette, Wagner, Kathryn, Manousakis, Georgios, Amato, Anthony, Butterfield, Russell, Shieh, Perry, Wicklund, Matthew, Gamez, Josep, Bodkin, Cynthia, Pestronk, Alan, Weihl, Conrad, Vilchez-Padilla, Juan, Johnson, Nicholas, Mathews, Katherine, Miller, Barry, Leneus, Ashley, Fowler, Marcie, van de Rijn, Marc, and Attie, Kenneth

Subjects
FSHD, controlled trial, facioscapulohumeral muscular dystrophy, randomized, Adolescent, Adult, Cytomegalovirus Infections, Humans, Magnetic Resonance Imaging, Muscle Contraction, Muscle, Skeletal, Muscular Dystrophy, Facioscapulohumeral
Abstract

INTRODUCTION/AIMS: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD. METHODS: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated. RESULTS: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P

Published
2022

5. Randomized Phase 2 Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease

Author

Thomas, Florian P, Brannagan, Thomas H, Butterfield, Russell J, Desai, Urvi, Habib, Ali A, Herrmann, David N, Eichinger, Katy J, Johnson, Nicholas E, Karam, Chafic, Pestronk, Alan, Quinn, Colin, Shy, Michael E, Statland, Jeffrey M, Subramony, Sub H, Walk, David, Stevens-Favorite, Katherine, Miller, Barry, Leneus, Ashley, Fowler, Marcie, van de Rijn, Marc, and Attie, Kenneth M

Subjects
Rare Diseases, Clinical Trials and Supportive Activities, Charcot-Marie-Tooth Disease, Neurosciences, Clinical Research, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo determine whether locally acting ACE-083 is safe, well tolerated, and increases muscle volume, motor function, and quality of life (QoL) in adults with Charcot-Marie-Tooth disease (CMT) type 1.MethodsThis phase 2 study enrolled adults with CMT1 or CMTX (N=63). Part 1 was open-label and evaluated safety and tolerability of different dose levels of ACE-083 for use in Part 2. Part 2 was a randomized, placebo-controlled, 6-month study of 240 mg/muscle ACE-083 injected bilaterally in the tibialis anterior muscle, followed by a 6-month, open-label extension in which all patients received ACE-083. Pharmacodynamic endpoints included total muscle volume (TMV; primary endpoint), contractile muscle volume (CMV), and fat fraction. Additional secondary endpoints included 6-minute walk test, 10-meter walk/run, muscle strength, and QoL. Safety was assessed with treatment-emergent adverse events (TEAEs) and clinical laboratory tests.ResultsIn Part 1 (n=18), ACE-083 was generally safe and well tolerated at all dose levels, with no serious AEs, TEAEs ≥Grade 3, or death reported. In Part 2 (n=45 enrolled, n=44 treated), there was significantly greater change in TMV with ACE-083 compared with placebo (LS mean difference: 13.5%; p = 0.0096). There was significant difference between ACE-083 and placebo for CMV and change in ankle dorsiflexion strength. Fat fraction and all other functional outcomes were not significantly improved by ACE-083. Moderate-to-mild injection-site reactions were the most common TEAEs.ConclusionsDespite significantly increased TMV and CMV, patients with CMT receiving ACE-083 in tibialis anterior muscles did not demonstrate greater functional improvement compared with those receiving placebo.Classification of evidenceThis study provides Class II evidence that intramuscular ACE-083 is safe, well tolerated, and increases total muscle volume after 6 months of treatment in adults with CMT1 or CMTX.

Published
2022

6. Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Author

Granit, Volkan, Steele, Julie, Levy, Wendy, Paredes, Maria Elena, Hernandez, Jessica, Bilsker, Martin, Szacka, Katarzyna, Ronert, Adam, Jablońska, Dorota, Łuczak, Alina Zuzanna, Chaverri, Delia, Janse van Mantgem, Mark R, Bunte, Tommy M, Broere, Bianca, de Fockert, Arianne, Sanchez-Tejerina, Daniel, Landabaso, Carmen, Calvo, Andrea, Moglia, Cristina, Manera, Umberto, Canosa, Antonio, Vasta, Rosario, Salamone, Paolina, Fuda, Giuseppe, DeMarco, Giovanni, Casale, Federico, ME Forsberg, Karin, Winroth, Ivar, Almgren Stenberg, Erica, Holmgren, Monica, Amador, Maria del Mar, Lenglet, Timothee, Querin, Giorgia, Coudoin, Sylvie, Pavlakis, Pantelis, Holzberg, Shara, Sideri, Riccardo, Marinou, Kalliopi, Czarnecki, Maciej, Ługiewicz, Renata, Biel-Czarnecka, Marta, Boczkowska, Marcelina, Schotte, Caroline, Vynckier, Jan, Van Daele, Sien, Claeys, Thomas, Delmotte, Koen, Swinnen, Bart, Serrien, Anouk, D'Hondt, Ann, Lamaire, Nikita, Debien, Elisa, Jones, Sarah, Vachon, Chris, Grogan, James, Solorzano, Guillermo, Crowell, Allison, Rakocevic, Goran, Wagoner, Mary, Alma, Osmanovic, Flavia, Wiehler, Sonja, Körner, Olivia, Schreiber-Katz, Camilla, Wohnrade, Anastasia, Sarikidi, Carola, Kassebaum, Chantal, Fischer, Adamo, Ashley, Turcotte, Nicole, Duncan, Jessie, Turner, Ivone, Elman, Lauren, Massie, Rami, Berube, Maxime, Saunders, Natalie, Salmon, Kristiana, Foucher, Juliette, Agessandro, Abrahao, Shirley, Pham, Jahan, Mookshah, Phung, Liane, Statland, Jeffrey, Jawdat, Omar, Dimachkie, Mazen, Pasnoor, Mamatha, Farmakidis, Constantine, Heim, Andrew, Lillig, Katie, Lackey, Alyssa, Weber, Markus, Kurz, Martina, Levine, Todd, Benatar, Michael, Hansen, Thomas, Rom, Dror, Geist, Marie A, Blaettler, Thomas, Camu, William, Kuzma-Kozakiewicz, Magdalena, van den Berg, Leonard H, Morales, Raul Juntas, Chio, Adriano, Andersen, Peter M, Pradat, Pierre-Francois, Lange, Dale, Van Damme, Philip, Mora, Gabriele, Grudniak, Mariusz, Elliott, Matthew, Petri, Susanne, Olney, Nicholas, Ladha, Shafeeq, Goyal, Namita A, Meyer, Thomas, Hanna, Michael G, Quinn, Colin, Genge, Angela, Zinman, Lorne, Jabari, Duaa, Shoesmith, Christen, Ludolph, Albert C, Neuwirth, Christoph, Nations, Sharon, Shefner, Jeremy M, Turner, Martin R, Wuu, Joanne, Bennett, Richard, Dang, Hoang, and Sundgreen, Claus

Published
2024
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7. Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial

Author

Tawil, Rabi, Wagner, Kathryn R, Hamel, Johanna I, Leung, Doris G, Statland, Jeffrey M, Wang, Leo H, Genge, Angela, Sacconi, Sabrina, Lochmüller, Hanns, Reyes-Leiva, David, Diaz-Manera, Jordi, Alonso-Perez, Jorge, Muelas, Nuria, Vilchez, Juan J, Pestronk, Alan, Gibson, Summer, Goyal, Namita A, Hayward, Lawrence J, Johnson, Nicholas, LoRusso, Samantha, Freimer, Miriam, Shieh, Perry B, Subramony, S H, van Engelen, Baziel, Kools, Joost, Leinhard, Olof Dahlqvist, Widholm, Per, Morabito, Christopher, Moxham, Christopher M, Cadavid, Diego, Mellion, Michelle L, Odueyungbo, Adefowope, Tracewell, William G, Accorsi, Anthony, Ronco, Lucienne, Gould, Robert J, Shoskes, Jennifer, Rojas, Luis Alejandro, and Jiang, John G

Published
2024
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8. Patient reported quality of life in limb girdle muscular dystrophy

Author

Kovalchick, Laurel V, Bates, Kameron, Statland, Jeffrey, Weihl, Conrad, Kang, Peter B, Lowes, Linda P, Mozaffar, Tahseen, Straub, Volker, Wicklund, Matthew, Heatwole, Chad, and Johnson, Nicholas E

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Intellectual and Developmental Disabilities (IDD), Muscular Dystrophy, Brain Disorders, Clinical Research, Rare Diseases, Management of diseases and conditions, 7.1 Individual care needs, Adolescent, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Muscle Weakness, Muscular Dystrophies, Limb-Girdle, Patient Reported Outcome Measures, Phenotype, Quality of Life, Registries, Surveys and Questionnaires, Young Adult, Quality of life, Limb girdle muscular dystrophy, Patient report, Dysferlin, Calpain-3, FKRP, Dysferlin, Calpain-3, Medical Physiology, Neurology & Neurosurgery, Clinical sciences, Biological psychology
Abstract

This study determined the frequency and impact of symptoms on quality of life in patients diagnosed with limb girdle muscular dystrophy (LGMD). Participants with a diagnosis of LGMD in registries based at the Coalition to Cure Calpain-3, the Jain foundation, and the Global FKRP Registry competed a survey to report the frequency and relative impact of themes and symptoms of LGMD. Frequency, mean impact, and population impact scores were calculated, and responses were categorized by age, symptom duration, gender, employment status, use of assistive devices, and LGMD subtypes. 134 participants completed the survey. The most prevalent themes included an inability to do activities (100%), limitation with mobility (99.3%), and lower extremity weakness (97.0%). Themes with the greatest impact were: limitations with mobility, lower extremity weakness, and an inability to do activities. Symptom duration and the use of assistive devices were associated with the presence of multiple themes. Employment was associated with the impact of several themes with no differences in frequency. The prevalence and impact of these themes vary in the LMGD population. The most prevalent and impactful themes were related to weakness, but additional concerns related to emotional challenges should also be considered in clinical and research settings.

Published
2022

9. Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study.

Author

Rudnicki, Stacy A, Andrews, Jinsy A, Duong, Tina, Cockroft, Bettina M, Malik, Fady I, Meng, Lisa, Wei, Jenny, Wolff, Andrew A, Genge, Angela, Johnson, Nicholas E, Tesi-Rocha, Carolina, Connolly, Anne M, Darras, Basil T, Felice, Kevin, Finkel, Richard S, Shieh, Perry B, Mah, Jean K, Statland, Jeffrey, Campbell, Craig, Habib, Ali A, Kuntz, Nancy L, Oskoui, Maryam, and Day, John W

Subjects
Muscle, Skeletal, Humans, Muscular Atrophy, Spinal, Troponin I, Drugs, Investigational, Cohort Studies, Double-Blind Method, Adolescent, Adult, Aged, Middle Aged, Child, Female, Male, Young Adult, Walk Test, Reldesemtiv, pharmacodynamics, pharmacokinetics, six-minute walk test, spinal muscular atrophy clinical trial, Clinical Research, Clinical Trials and Supportive Activities, Rare Diseases, 6.1 Pharmaceuticals, Neurosciences, Pharmacology and Pharmaceutical Sciences, Public Health and Health Services, Neurology & Neurosurgery
Abstract

This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H2O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (Cmax > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H2O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations.

Published
2021

10. Safety and efficacy of arimoclomol for inclusion body myositis: a multicentre, randomised, double-blind, placebo-controlled trial

Author

Dimachkie, Mazen, Statland, Jeffrey, Pasnoor, Mamatha, Jawdat, Omar, Heim, Andrew, Ciersdorff, Ali, Sasidharan, Sandhya, Currence, Melissa, Levine, Todd, Otutoa, Rebecca, Cooper, Angelina, Mozaffar, Tahseen, Habib, Ali, Cauchi, Jonathan, Ung, Shannon, Mathew, Veena, Hernandez, Isela, Gibson, Summer, Bromberg, Mark, Mahoney, Kyle, Neate, Crystal, Janecki, Teresa, Papadakis, Mike, Freimer, Miriam, Kaschalk, MacKenzie, Heintzman, Sarah, Wicklund, Matthew, Baines, Brenna, Vareldzis, Alexa, Hyslop, Emily, Blume, Brianna, Ciafaloni, Emma, Luebbe, Elizabeth, Eichinger, Katy, Martens, William, Gregory, Stephanie, Janciuras, Joanne, Amato, Anthony, Doughty, Christopher, Roe, Kristen, Flynn, Patricia, Russo, Emily, Lloyd, Thomas, Albayda, Jemima, Tiniakou, Eleni, Thomas, Simone, Jones, Sarah, Solorzano, Guillermo, Elliott, Matthew, Burns, Ted, Crowell, Allison, Eggleston, Deborah, Wagoner, Mary, Shaibani, Aziz, Oates, Chantae, Machado, Pedro, Hanna, Michael, Greensmith, Linda, Ahmed, Mhoriam, Vivekanandam, Vinojini, Appleby, Matthew, Ransley, George, Eshun, Edwin Eshun, Skorupinska, Iwona, Germain, Louise, Laxa, Ana Marie, Pontes, Joana Roca, Bellin, Anna, Anifowoshe, Dolapo, Machado, Pedro M, McDermott, Michael P, Blaettler, Thomas, Sundgreen, Claus, Amato, Anthony A, Gibson, Summer B, Jones, Sarah M, Levine, Todd D, Lloyd, Thomas E, Shaibani, Aziz I, Rosholm, Anders, Carstensen, Tim Dehli, Bonefeld, Karen, Jørgensen, Anders Nørkær, Phonekeo, Karina, Heim, Andrew J, Herbelin, Laura, Barohn, Richard J, Hanna, Michael G, and Dimachkie, Mazen M

Published
2023
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11. A Randomized, Double-Blind, Placebo-Controlled, Global Phase 3 Study of Edasalonexent in Pediatric Patients with Duchenne Muscular Dystrophy: Results of the PolarisDMD Trial.

Author

Lee Sweeney, H, Finanger, Erika, Neil Knierbein, Erin, Wagner, Kathryn, Mathews, Katherine, Marks, Warren, Statland, Jeffrey, Nance, Jessica, McMillan, Hugh, McCullagh, Gary, Tian, Cuixia, Ryan, Monique, ORourke, Declan, Müller-Felber, Wolfgang, Tulinius, Mar, Burnette, W, Nguyen, Cam-Tu, Vijayakumar, Kayal, Johannsen, Jessika, Phan, Han, Eagle, Michelle, MacDougall, James, Mancini, Maria, Donovan, Joanne, Finkel, Richard, and McDonald, Craig

Subjects
CAT-1004, Duchenne muscular dystrophy, NF-κB, age effects, edasalonexent, Administration, Oral, Arachidonic Acids, Child, Child, Preschool, Double-Blind Method, Humans, Male, Muscular Dystrophy, Duchenne, NF-kappa B, Salicylamides
Abstract

BACKGROUND: Edasalonexent (CAT-1004) is an orally-administered novel small molecule drug designed to inhibit NF-κB and potentially reduce inflammation and fibrosis to improve muscle function and thereby slow disease progression and muscle decline in Duchenne muscular dystrophy (DMD). OBJECTIVE: This international, randomized 2 : 1, placebo-controlled, phase 3 study in patients ≥4 -

Published
2021

13. Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial

Author

Thornton, Charles A, Moxley, Richard Thomas, III, Eichinger, Katy, Heatwole, Chad, Mignon, Laurence, Arnold, W David, Ashizawa, Tetsuo, Day, John W, Dent, Gersham, Tanner, Matthew K, Duong, Tina, Greene, Ericka P, Herbelin, Laura, Johnson, Nicholas E, King, Wendy, Kissel, John T, Leung, Doris G, Lott, Donovan J, Norris, Daniel A, Pucillo, Evan M, Schell, Wendy, Statland, Jeffrey M, Stinson, Nikia, Subramony, Sub H, Xia, Shuting, Bishop, Kathie M, and Bennett, C Frank

Published
2023
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14. Zilucoplan in immune-mediated necrotising myopathy: a phase 2, randomised, double-blind, placebo-controlled, multicentre trial

Author

Amato, Anthony A., Benveniste, Olivier, Biliciler, Suur, Chinoy, Hector, Dimachkie, Mazen M., Edmundson, Christyn, Freimer, Miriam, Geraci, Anthony, Hussain, Yessar, Machado, Pedro, Mammen, Andrew L., Mozaffar, Tahseen, Soltanzadeh, Payam, Suresh, Niraja, van der Kooi, Anneke, Allenbach, Yves, Appleby, Matthew, Barohn, Richard J, Champtiaux, Nicolas, Doughty, Christopher, Farias, Jerrica, Farmakidis, Constantine, Habib, Ali A., Karam, Chafic, Lilleker, James, Lorusso, Samantha, Pasnoor, Mamatha, Pinal-Fernandez, Iago, Querin, Giorgia, Raaphorst, Joost, Ransley, George, Saba, Sami, Sheikh, Kazim, Snedden, Andrew, Statland, Jeffrey, Vu, Tuan, Mammen, Andrew L, Amato, Anthony A, Dimachkie, Mazen M, Lilleker, James B, Boroojerdi, Babak, Vanderkelen, Mark, Delicha, Eumorphia Maria, Koendgen, Harold, Farzaneh-Far, Ramin, Duda, Petra W, and Sayegh, Camil

Published
2023
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15. Rasagiline for amyotrophic lateral sclerosis: A randomized, controlled trial

Author

Statland, Jeffrey M, Moore, Dan, Wang, Yunxia, Walsh, Maureen, Mozaffar, Tahseen, Elman, Lauren, Nations, Sharon P, Mitsumoto, Hiroshi, Fernandes, J Americo, Saperstein, David, Hayat, Ghazala, Herbelin, Laura, Karam, Chafic, Katz, Jonathan, Wilkins, Heather M, Agbas, Abdulbaki, Swerdlow, Russell H, Santella, Regina M, Dimachkie, Mazen M, Barohn, Richard J, and Consortium, The Rasagiline Investigators of the Muscle Study Group and Western ALS

Subjects
Clinical Research, Clinical Trials and Supportive Activities, ALS, Neurodegenerative, Neurosciences, Brain Disorders, Rare Diseases, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Neurological, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Double-Blind Method, Female, Humans, Indans, Male, Middle Aged, Neuroprotective Agents, Outcome Assessment, Health Care, Quality of Life, Retrospective Studies, Severity of Illness Index, Treatment Outcome, United States, Young Adult, amyotrophic lateral sclerosis, biomarker, MAO-B inhibitor, motor neuron disease, randomized, controlled clinical trial, rasagiline, Rasagiline Investigators of the Muscle Study Group and Western ALS Consortium, Medical and Health Sciences, Neurology & Neurosurgery
Abstract

Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with possible neuroprotective effects in patients with amyotrophic lateral sclerosis (ALS). We performed a randomized, double-blind, placebo-controlled trial of 80 ALS participants with enrichment of the placebo group with historical controls (n = 177) at 10 centers in the United States. Participants were randomized in a 3:1 ratio to 2 mg/day rasagiline or placebo. The primary outcome was average slope of decline on the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures included slow vital capacity, survival, mitochondrial and molecular biomarkers, and adverse-event reporting. There was no difference in the average 12-month ALSFRS-R slope between rasagiline and the mixed placebo and historical control cohorts. Rasagiline did not show signs of drug-target engagement in urine and blood biomarkers. Rasagiline was well tolerated with no serious adverse events. Rasagiline did not alter disease progression compared with controls over 12 months of treatment. Muscle Nerve 59:201-207, 2019.

Published
2019

16. Review of the Diagnosis and Treatment of Periodic Paralysis

Author

Statland, Jeffrey M, Fontaine, Bertrand, Hanna, Michael G, Johnson, Nicholas E, Kissel, John T, Sansone, Valeria A, Shieh, Perry B, Tawil, Rabi N, Trivedi, Jaya, Cannon, Stephen C, and Griggs, Robert C

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Prevention, Nutrition, Genetics, Rare Diseases, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Acetazolamide, Andersen Syndrome, Anti-Arrhythmia Agents, Behavior Therapy, Carbonic Anhydrase Inhibitors, Diuretics, Diuretics, Potassium Sparing, Humans, Hydrochlorothiazide, Hypokalemic Periodic Paralysis, Paralyses, Familial Periodic, Paralysis, Hyperkalemic Periodic, Potassium, acetazolamide, Andersen-Tawil syndrome, channelopathies, dichlorphenamide, periodic paralyses, review, treatment, Medical and Health Sciences, Neurology & Neurosurgery, Biological sciences, Biomedical and clinical sciences
Abstract

Periodic paralyses (PPs) are rare neuromuscular disorders caused by mutations in skeletal muscle sodium, calcium, and potassium channel genes. PPs include hypokalemic paralysis, hyperkalemic paralysis, and Andersen-Tawil syndrome. Common features of PP include autosomal dominant inheritance, onset typically in the first or second decades, episodic attacks of flaccid weakness, which are often triggered by diet or rest after exercise. Diagnosis is based on the characteristic clinic presentation then confirmed by genetic testing. In the absence of an identified genetic mutation, documented low or high potassium levels during attacks or a decrement on long exercise testing support diagnosis. The treatment approach should include both management of acute attacks and prevention of attacks. Treatments include behavioral interventions directed at avoidance of triggers, modification of potassium levels, diuretics, and carbonic anhydrase inhibitors. Muscle Nerve 57: 522-530, 2018.

Published
2018

17. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial

Author

Behin, Anthony, Boentert, Matthias, Carvalho, Gerson, Chahin, Nizar, Charrow, Joel, Deegan, Patrick, Durmus Tekce, Hacer, Duval, Fanny, Genge, Angela, Gutmann, Ludwig, Henderson, Robert D, Hennermann, Julia B, Hiwot, Tarekegn, Hughes, Derralynn, Karaa, Amel, Karam, Chafic, Kautzky-Willer, Alexandra, Komaki, Hirofumi, Laforet, Pascal, Longo, Nicola, Malinova, Vera, Maré, Ricardo, Maxit, Clarisa, Mengel, Eugen, Moggio, Maurizio Gualtiero, Molnár, Mária Judit, Mongini, Tiziana Enrica, Nadaj-Pakleza, Aleksandra, Nascimento Osorio, Andres, Noury, Jean-Baptiste, Oliveira, Acary Souza Bulle, Parman, Yesim, Pena, Loren, Remiche, Gauthier, Sciacco, Monica, Shieh, Perry B, Smith, Cheryl, Stulnig, Thomas, Taithe, Frederic, Tard, Céline, Tarnopolsky, Mark, Vorgerd, Matthias, Whitley, Chester, Young, Peter, Alonso-Pérez, Jorge, Altemus, Patricia, Aubé-Nathier, Anne-Catherine, Avelar, Jennifer B, Bailey, Carrie, Bekircan-Kurt, Can Ebru, Billy, Jenny, Boschi, Silvia, Brown, Kathryn E, Carrera Garcia, Laura, Chase, Lauren, Cirne, Hamilton, Danjoux, Loïc, Davion, Jean-Baptiste, DeArmey, Stephanie, Fedotova, Ekaterina, Gandolfo, Eve, Grosz, Zoltan, Guellec, Dewi, Guettsches, Anne-Katrin, Guglieri, Michela, Hatcher, Erin, Helms, Sina, Hufgard-Leitner, Miriam, Klyushnikov, Sergey A., Langton, Jacqui, Linková, Lenka, Mavroudakis, Nicolas, Mazurová, Stella, Mori, Madoka, Müller-Miny, Louisa, Musumeci, Olimpia, Nance, Christopher S, Natera-de Benito, Daniel, Neel, Robert, Niizawa, Gabriela A, Noll, Lauren, Ortega, Erik, Pasnoor, Mamatha, Pautot, Vivien, Potulska-Chromik, Anna, Pugliese, Alessia, Questienne, Claire, Ramos Lopes, Margarida, Reyes-Leiva, David, Riedl, Michaela, Rugiero, Marcelo Francisco, Salort-Campana, Emmanuelle, Sgobbi Souza, Paulo Victor, Sole, Guilhem, Solera, Luca, Souto Lopes, Suzara, Specht, Sabine, Statland, Jeffrey, Swenson, Andrea, Tan, Chong Yew, Tizon, Sónia, van der Beek, N A M E, van Kooten, Harmke A., Wencel, Marie, Wenninger, Stephan, Zagnoli, Fabien, Diaz-Manera, Jordi, Kishnani, Priya S, Kushlaf, Hani, Ladha, Shafeeq, Mozaffar, Tahseen, Straub, Volker, Toscano, Antonio, van der Ploeg, Ans T, Berger, Kenneth I, Clemens, Paula R, Chien, Yin-Hsiu, Day, John W, Illarioshkin, Sergey, Roberts, Mark, Attarian, Shahram, Borges, Joao Lindolfo, Bouhour, Francoise, Choi, Young Chul, Erdem-Ozdamar, Sevim, Goker-Alpan, Ozlem, Kostera-Pruszczyk, Anna, Haack, Kristina An, Hug, Christopher, Huynh-Ba, Olivier, Johnson, Judith, Thibault, Nathan, Zhou, Tianyue, Dimachkie, Mazen M, and Schoser, Benedikt

Published
2021
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18. Ataluren Slows the Decline of Muscle Function in Patents with nmDMD: A Meta-analysis of Three Randomized, Double-blind, Placebo-controlled Trials (P3-11.002)

Author

Jong, Yuh-Jyh, primary, Karachunski, Peter, additional, Statland, Jeffrey, additional, Lorentzos, Michelle, additional, Cairns, Anita, additional, Takeshima, Yasuhiro, additional, Haginoya, Kazuhiro, additional, Penematsa, Vinay, additional, Chou, Connie, additional, Williams, Paula, additional, and Werner, Christian, additional

Published
2024
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19. Ataluren Delays Clinically Meaningful Milestones of Decline in 6WMD in Patients with nmDMD from Study 041, a Phase 3, Placebo-controlled Trial (S21.001)

Author

Wu, Shiwen, primary, Gulati, Sheffali, additional, Komaki, Hirofumi, additional, Escobar-Cedillo, Rosa E., additional, Kostera-Prusczyk, Anna, additional, Shin, Jin-Hong, additional, Haginoya, Kazuhiro, additional, Penematsa, Vinay, additional, Chou, Connie, additional, Williams, Paula, additional, Werner, Christian, additional, and Statland, Jeffrey, additional

Published
2024
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23. Health related quality of life in young, steroid-naïve boys with Duchenne muscular dystrophy

Author

Straub, Volker, Childs, Anne-Marie, Ciafaloni, Emma, Shieh, Perry B., Spinty, Stefan, Butterfield, Russell J., Horrocks, Iain, Roper, Helen, Maggi, Lorenzo, Baranello, Giovanni, Flanigan, Kevin M., Kuntz, Nancy L., Manzur, Adnan Y., Darras, Basil T., Kang, Peter, Mah, Jean K., Mongini, Tiziana, Ricci, Federica, Morrison, Leslie, Krzesniak-Swinarska, Monika, von der Hagen, Maja, Finkel, Richard S., Kumar, Ashutosh, Wicklund, Matthew, McDonald, Craig M., Henricson, Erik K., Schara-Schmidt, Ulrike, Wilichowski, Ekkehard, Barohn, Richard J., Statland, Jeffrey, Kirschner, Janbernd, Vita, Giuseppe, Vita, Gian Luca, Howard, James F., Jr., Hughes, Imelda, McMillan, Hugh J., Pegoraro, Elena, Bello, Luca, Burnette, W. Bryan, Thangarajh, Mathula, Chang, Taeun, Campbell, Craig, McColl, Elaine, McDermott, Michael P., Martens, William B., Guglieri, Michela, and Griggs, Robert C.

Published
2021
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25. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial

Author

De Bleecker, Jan L., De Koning, Kathy, De Mey, Katrien, De Pue, Annelien, Mercelis, Rudolf, Wyckmans, Maren, Vinck, Caroline, Wagemaekers, Linda, Baets, Jonathan, Ng, Eduardo, Shabanpour, Jafar, Daniyal, Lubna, Mannan, Shabber, Katzberg, Hans D., Genge, Angela, Siddiqi, Zaeem, Junkerová, Jana, Horakova, Jana, Reguliova, Katerina, Tyblova, Michaela, Jurajdova, Ivana, Novakova, Iveta, Jakubikova, Michala, Pitha, Jiri, Vohanka, Stanislav, Havelkova, Katerina, Horak, Tomas, Bednarik, Josef, Horakova, Mageda, Meisel, Andreas, Remstedt, Dike, Heibutzki, Claudia, Kohler, Siegfried, Gerischer, Lea, Hoffman, Sarah, Stascheit, Frauke, Vissing, John, Zafirakos, Lizzie, Khatri, Kuldeep Kumar, Autzen, Anne, Godtfeldt Stemmerik, Mads Peter, Andersen, Henning, Attarian, Shahram, Salort-Campana, Emmanuelle, Delmont, Emilien, Grapperon, Aude-Marie, Kouton, Ludivine, Tsiskaridze, Alexander, Rózsa, Csilla, Jakab, Gedeonne Margo, Toth, Szilvia, Szabo, Gyorgyi, Bors, David, Szabo, Eniko, Campanella, Angela, Vanoli, Fiammetta, Frangiamore, Rita, Antozzi, Carlo, Bonanno, Silvia, Maggi, Lorenzo, Giossi, Riccardo, Saccà, Francesco, Marsili, Angela, Pane, Chiara, Puorro, Giorgia, Reia, Antonio, Antonini, Giovanni, Alfieri, Girolamo, Morino, Stefania, Garibaldi, Matteo, Fionda, Laura, Leonardi, Luca, Konno, Shingo, Uzawa, Akiyuki, Sakuma, Kaoru, Watanabe, Chiho, Ozawa, Yukiko, Yasuda, Manato, Onishi, Yosuke, Samukawa, Makoto, Tsuda, Tomoko, Suzuki, Yasushi, Ishida, Sayaka, Watanabe, Genya, Takahashi, Masanori, Nakamura, Hiroko, Sugano, Erina, Kubota, Tomoya, Imai, Tomihiro, Suzuki., Mari, Mori, Ayako, Yamamoto, Daisuke, Ikeda, Kazuna, Hisahara, Shin, Masuda, Masayuki, Takaki, Miki, Minemoto, Kanako, Ido, Nobuhiro, Naito, Makiko, Okubo, Yoshihiko, Sugimoto, Takamichi, Takematsu, Yuka, Kamei, Ayumi, Shimizu, Mihiro, Naito, Hiroyuki, Nomura, Eiichi, Van Heur, Marjolein, Peters, Anne-Marie, Tannemaat, Martijn, Ruiter, Annabel, Keene, Kevin, Halas, Marek, Szczudlik, Andrzej, Pinkosz, Marta, Frasinska, Monika, Zwolinska, Grazyna, Kostera-Pruszczyk, Anna, Golenia, Aleksandra, Szczudlik, Piotr, Szczechowski, Lech, Pasko, Aneta, Poverennova, Irina, Urtaeva, Lubov, Kuznetsova, Nadezhda, Romanova, Tatiana, Nadezhda, Malkova, Lapochka, Elena, Korobko, Denis, Vergunova, Ilona, Melnikova, Anna, Bulatova, Ekaterina, Antipenko, Elena, Basta, Ivana, Bozovic, Ivo, Lavrnic, Dragana, Stojanovic, Vidosava Rakocevic, Beydoun, Said, Akhter, Salma, Malekniazi, Ali, Darki, Leila, Pimentel, Norianne, Cannon, Victoria, Chopra, Manisha, Traub, Rebecca, Mozaffar, Tahseen, Hernandez, Isela, Turner, Ivonne, Habib, Ali, Goyal, Namita, Kak, Manisha, Velasquez, Erik, Lam, Lucy, Suresh, Niraja, Farias, Jerrica, Jones, Sarah, Wagoner, Mary, Eggleston, Debbie, Bertorini, Tulio, Benzel, Cindy, Henegar, Robert, Pillai, Rekha, Bharavaju-Sanka, Ratna, Paiz, Carolyn, Jackson, Carlayne, Ruzhansky, Katherine, Dimitrova, Diana, Visser, Amy, Chahin, Nizar, Levine, Todd, Lisak, Robert, Jia, Kelly, Mada, Flicia, Bernitsas, Evanthia, Pasnoor, Mamatha, Roath, Katherine, Colgan, Samantha, Currence, Melissa, Heim, Andrew, Barohn, Richard, Dimachkie, Mazen, Statland, Jeffrey, Jawdat, Omar, Jabari, Duaa, Farmakidis, Constantine, Gilchrist, James, Li, Yuebing, Caristo, Irys, Hastings, Debbie, Morren, John Anthony, Weiss, Michael, Muppidi, Srikanth, Nguyen, Tia, Welsh, Lesly, So, Yuen, Goyal, Neelam, Pulley, Michael, Bailey, Cathy, Quraishi, Zubair, Berger, Alan, Sahagian, Gregory, Camberos, Yasmin, Frishberg, Benjamin, Howard, James F, Jr, Bril, Vera, Vu, Tuan, Karam, Chafic, Peric, Stojan, Margania, Temur, Murai, Hiroyuki, Bilinska, Malgorzata, Shakarishvili, Roman, Smilowski, Marek, Guglietta, Antonio, Ulrichts, Peter, Vangeneugden, Tony, Utsugisawa, Kimiaki, Verschuuren, Jan, and Mantegazza, Renato

Published
2021
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26. Autosomal dominant in cis D4Z4 repeat array duplication alleles in facioscapulohumeral dystrophy

Author

Neurologen, Brain, Lemmers, Richard J.L.F., Butterfield, Russell, Van Der Vliet, Patrick J., De Bleecker, Jan L., Van Der Pol, Ludo, Dunn, Diane M., Erasmus, Corrie E., D'Hooghe, Marc, Verhoeven, Kristof, Balog, Judit, Bigot, Anne, Van Engelen, Baziel, Statland, Jeffrey, Bugiardini, Enrico, Van Der Stoep, Nienke, Evangelista, Teresinha, Marini-Bettolo, Chiara, Van Den Bergh, Peter, Tawil, Rabi, Voermans, Nicol C., Vissing, John, Weiss, Robert B., Van Der Maarel, Silvere M., Neurologen, Brain, Lemmers, Richard J.L.F., Butterfield, Russell, Van Der Vliet, Patrick J., De Bleecker, Jan L., Van Der Pol, Ludo, Dunn, Diane M., Erasmus, Corrie E., D'Hooghe, Marc, Verhoeven, Kristof, Balog, Judit, Bigot, Anne, Van Engelen, Baziel, Statland, Jeffrey, Bugiardini, Enrico, Van Der Stoep, Nienke, Evangelista, Teresinha, Marini-Bettolo, Chiara, Van Den Bergh, Peter, Tawil, Rabi, Voermans, Nicol C., Vissing, John, Weiss, Robert B., and Van Der Maarel, Silvere M.

Published
2024

27. Reldesemtiv in Patients with Spinal Muscular Atrophy: a Phase 2 Hypothesis-Generating Study

Author

Rudnicki, Stacy A., Andrews, Jinsy A., Duong, Tina, Cockroft, Bettina M., Malik, Fady I., Meng, Lisa, Wei, Jenny, Wolff, Andrew A., Genge, Angela, Johnson, Nicholas E., Tesi-Rocha, Carolina, Connolly, Anne M., Darras, Basil T., Felice, Kevin, Finkel, Richard S., Shieh, Perry B., Mah, Jean K., Statland, Jeffrey, Campbell, Craig, Habib, Ali A., Kuntz, Nancy L., Oskoui, Maryam, and Day, John W.

Published
2021
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28. Outcomes after intervention for enteral nutrition in patients with amyotrophic lateral sclerosis in multidisciplinary clinics.

Author

Fullam, Timothy, Hunt, Suzanne L., Han, Madison, Denesia, Jacob, Chandrashekhar, Swathy, Jawdat, Omar, Piccione, Ezequiel, Fernandes, J. Americo, and Statland, Jeffrey

Abstract

Introduction/Aims: Patients with amyotrophic lateral sclerosis (ALS) are susceptible to malnutrition, with appropriate management of nutritional interventions an active area of investigation. We sought to determine the impact of gastrostomy tube placement in ALS patients, exploring the correlation between forced vital capacity (FVC), malnutrition, and perioperative complications. Methods: A retrospective review was performed of clinically diagnosed ALS patients treated at two multidisciplinary clinics (University of Kansas, University of Nebraska) from January 2009 to September 2020 who were referred for gastrostomy. Data collected included demographics, disease characteristics, and key gastrostomy related dates/outcomes. Results: Two hundred thirty‐nine patients were included with a median age of 65 years and median of 589 days from symptom onset to gastrostomy (interquartile range, 404–943). The population was predominantly Non‐Hispanic White with bulbar‐onset ALS. 30‐day mortality was 4% and 30‐day morbidity was 13%. Weight loss, body mass index, and predicted FVC at placement showed no increased 30‐day morbidity or mortality association. Bulbar‐onset ALS patients exhibited higher overall mortality postplacement than limb onset (odds ratio: 1.85, 95% confidence interval: 1.03–3.33). There was a 5% incidence of symptoms suggestive of refeeding syndrome. Discussion: Rates of major/minor complications and 30‐day mortality related to gastrostomy placement in our population were similar compared with prior studies in ALS. The lack of difference in outcomes based on FVC at procedure may suggest this is not predictive of outcome, or perhaps, high‐quality perioperative respiratory management. Alternative reasons may account for the increased morbidity and mortality of gastrostomy placement in the ALS population. [ABSTRACT FROM AUTHOR]

Published
2024
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29. A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis.

Author

Pasnoor, Mamatha, He, Jianghua, Herbelin, Laura, Burns, Ted M, Nations, Sharon, Bril, Vera, Wang, Annabel K, Elsheikh, Bakri H, Kissel, John T, Saperstein, David, Shaibani, J Aziz, Jackson, Carlayne, Swenson, Andrea, Howard, James F, Goyal, Namita, David, William, Wicklund, Matthew, Pulley, Michael, Becker, Mara, Mozaffar, Tahseen, Benatar, Michael, Pazcuzzi, Robert, Simpson, Ericka, Rosenfeld, Jeffrey, Dimachkie, Mazen M, Statland, Jeffrey M, Barohn, Richard J, and Methotrexate in MG Investigators of the Muscle Study Group

Subjects
Methotrexate in MG Investigators of the Muscle Study Group, Humans, Myasthenia Gravis, Methotrexate, Prednisone, Receptors, Cholinergic, Immunosuppressive Agents, Autoantibodies, Treatment Outcome, Severity of Illness Index, Area Under Curve, Double-Blind Method, Adult, Aged, Aged, 80 and over, Middle Aged, Canada, United States, Female, Male, Clinical Trials and Supportive Activities, Rare Diseases, Autoimmune Disease, Neurosciences, Clinical Research, Orphan Drug, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo determine the steroid-sparing effect of methotrexate (MTX) in patients with symptomatic generalized myasthenia gravis (MG).MethodsWe performed a 12-month multicenter, randomized, double-blind, placebo-controlled trial of MTX 20 mg orally every week vs placebo in 50 acetylcholine receptor antibody-positive patients with MG between April 2009 and August 2014. The primary outcome measure was the prednisone area under the dose-time curve (AUDTC) from months 4 to 12. Secondary outcome measures included 12-month changes of the Quantitative Myasthenia Gravis Score, the Myasthenia Gravis Composite Score, Manual Muscle Testing, the Myasthenia Gravis Quality of Life, and the Myasthenia Gravis Activities of Daily Living.ResultsFifty-eight patients were screened and 50 enrolled. MTX did not reduce the month 4-12 prednisone AUDTC when compared to placebo (difference MTX - placebo: -488.0 mg, 95% confidence interval -2,443.4 to 1,467.3, p = 0.26); however, the average daily prednisone dose decreased in both groups. MTX did not improve secondary measures of MG compared to placebo over 12 months. Eight participants withdrew during the course of the study (1 MTX, 7 placebo). There were no serious MTX-related adverse events. The most common adverse event was nonspecific pain (19%).ConclusionsWe found no steroid-sparing benefit of MTX in MG over 12 months of treatment, despite being well-tolerated. This study demonstrates the challenges of conducting clinical trials in MG, including difficulties with recruitment, participants improving on prednisone alone, and the need for a better understanding of outcome measure variability for future clinical trials.Classification of evidenceThis study provides Class I evidence that for patients with generalized MG MTX does not significantly reduce the prednisone AUDTC over 12 months of therapy.

Published
2016

31. A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot–Marie–Tooth type 1A

Author

Attarian, Shahram, Young, Peter, Brannagan, Thomas H., Adams, David, Van Damme, Philip, Thomas, Florian P., Casanovas, Carlos, Kafaie, Jafar, Tard, Céline, Walter, Maggie C., Péréon, Yann, Walk, David, Stino, Amro, de Visser, Marianne, Verhamme, Camiel, Amato, Anthony, Carter, Gregory, Magy, Laurent, Statland, Jeffrey M., and Felice, Kevin

Published
2021
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33. Regional and bilateral MRI and gene signatures in facioscapulohumeral dystrophy: implications for clinical trial design and mechanisms of disease progression.

Author

Wong, Chao-Jen, Friedman, Seth D, Snider, Lauren, Bennett, Sean R, Jones, Takako I, Jones, Peter L, Shaw, Dennis W W, Blemker, Silvia S, Riem, Lara, DuCharme, Olivia, Lemmers, Richard J F L, Maarel, Silvère M van der, Wang, Leo H, Tawil, Rabi, Statland, Jeffrey M, and Tapscott, Stephen J

Published
2024
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35. Longitudinal course of neurofilament light chain levels in amyotrophic lateral sclerosis—insights from a completed randomized controlled trial with rasagiline.

Author

Witzel, Simon, Statland, Jeffrey M., Steinacker, Petra, Otto, Markus, Dorst, Johannes, Schuster, Joachim, Barohn, Richard J., and Ludolph, Albert C.

Subjects
*AMYOTROPHIC lateral sclerosis, *RANDOMIZED controlled trials, *CYTOPLASMIC filaments, *CLUSTER randomized controlled trials, *DISEASE progression, *DISEASE duration
Abstract

Background and purpose: Rasagiline might be disease modifying in patients with amyotrophic lateral sclerosis (ALS). The aim was to evaluate the effect of rasagiline 2 mg/day on neurofilament light chain (NfL), a prognostic biomarker in ALS. Methods: In 65 patients with ALS randomized in a 3:1 ratio to rasagiline 2 mg/day (n = 48) or placebo (n = 17) in a completed randomized controlled multicentre trial, NfL levels in plasma were measured at baseline, month 6 and month 12. Longitudinal changes in NfL levels were evaluated regarding treatment and clinical parameters. Results: Baseline NfL levels did not differ between the study arms and correlated with disease progression rates both pre‐baseline (r = 0.64, p < 0.001) and during the study (r = 0.61, p < 0.001). NfL measured at months 6 and 12 did not change significantly from baseline in both arms, with a median individual NfL change of +1.4 pg/mL (interquartile range [IQR] −5.6, 14.2) across all follow‐up time points. However, a significant difference in NfL change at month 12 was observed between patients with high and low NfL baseline levels treated with rasagiline (high [n = 13], −6.9 pg/mL, IQR −20.4, 6.0; low [n = 18], +5.9 pg/mL, IQR −1.4, 19.7; p = 0.025). Additionally, generally higher longitudinal NfL variability was observed in patients with high baseline levels, whereas disease progression rates and disease duration at baseline had no impact on the longitudinal NfL course. Conclusion: Post hoc NfL measurements in completed clinical trials are helpful in interpreting NfL data from ongoing and future interventional trials and could provide hypothesis‐generating complementary insights. Further studies are warranted to ultimately differentiate NfL response to treatment from other factors. [ABSTRACT FROM AUTHOR]

Published
2024
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36. A longitudinal study of disease progression in facioscapulohumeral muscular dystrophy (FSHD).

Author

Varma, Anika, Todinca, Michael S., Eichinger, Katy, Heininger, Susanne, Dilek, Nuran, Martens, William, Tawil, Rabi, Statland, Jeffrey, Kissel, John T., McDermott, Michael P., and Heatwole, Chad

Abstract

Introduction/Aims: In preparation for clinical trials, it is important to better understand how disease burden changes over time in facioscapulohumeral muscular dystrophy (FSHD) and to assess the capability of select metrics to detect these changes. This study aims to evaluate FSHD disease progression over 1 year and to examine the sensitivity of several outcome measures in detecting changes during this interval. Methods: We conducted a 12‐month prospective observational study of 41 participants with FSHD. Participants were evaluated at baseline, 6 months, and 12 months with serial strength testing (manual muscle testing or MMT and maximum voluntary isometric contraction testing or MVICT), functional testing (FSHD‐Composite Outcome Measure or FSHD‐COM, FSHD Clinical Severity Score or CSS, and FSHD Evaluation Score or FES), sleep and fatigue assessments, lean body mass measurements, respiratory testing, and the FSHD‐Health Index patient‐reported outcome. Changes in these outcome measures were assessed over the 12‐month period. Associations between changes in outcome measures and both age and sex were also examined. Results: In a 12‐month period, FSHD participant function remained largely stable with a mild worsening of strength, measured by MMT and standardized MVICT scores, and a mild loss in lean body mass. Discussion: The abilities and disease burden of adults with FSHD are largely static over a 12‐month period with participants demonstrating a mild average reduction in some measures of strength. Selection of patients, outcome measures, and trial duration should be carefully considered during the design and implementation of future clinical studies involving FSHD patients. [ABSTRACT FROM AUTHOR]

Published
2024
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40. Safety and efficacy of arimoclomol for inclusion body myositis: a multicentre, randomised, double-blind, placebo-controlled trial

Author

Machado, Pedro M, primary, McDermott, Michael P, additional, Blaettler, Thomas, additional, Sundgreen, Claus, additional, Amato, Anthony A, additional, Ciafaloni, Emma, additional, Freimer, Miriam, additional, Gibson, Summer B, additional, Jones, Sarah M, additional, Levine, Todd D, additional, Lloyd, Thomas E, additional, Mozaffar, Tahseen, additional, Shaibani, Aziz I, additional, Wicklund, Matthew, additional, Rosholm, Anders, additional, Carstensen, Tim Dehli, additional, Bonefeld, Karen, additional, Jørgensen, Anders Nørkær, additional, Phonekeo, Karina, additional, Heim, Andrew J, additional, Herbelin, Laura, additional, Barohn, Richard J, additional, Hanna, Michael G, additional, Dimachkie, Mazen M, additional, Dimachkie, Mazen, additional, Statland, Jeffrey, additional, Pasnoor, Mamatha, additional, Jawdat, Omar, additional, Heim, Andrew, additional, Ciersdorff, Ali, additional, Sasidharan, Sandhya, additional, Currence, Melissa, additional, Levine, Todd, additional, Otutoa, Rebecca, additional, Cooper, Angelina, additional, Habib, Ali, additional, Cauchi, Jonathan, additional, Ung, Shannon, additional, Mathew, Veena, additional, Hernandez, Isela, additional, Gibson, Summer, additional, Bromberg, Mark, additional, Mahoney, Kyle, additional, Neate, Crystal, additional, Janecki, Teresa, additional, Papadakis, Mike, additional, Kaschalk, MacKenzie, additional, Heintzman, Sarah, additional, Baines, Brenna, additional, Vareldzis, Alexa, additional, Hyslop, Emily, additional, Blume, Brianna, additional, Luebbe, Elizabeth, additional, Eichinger, Katy, additional, Martens, William, additional, Gregory, Stephanie, additional, Janciuras, Joanne, additional, Amato, Anthony, additional, Doughty, Christopher, additional, Roe, Kristen, additional, Flynn, Patricia, additional, Russo, Emily, additional, Lloyd, Thomas, additional, Albayda, Jemima, additional, Tiniakou, Eleni, additional, Thomas, Simone, additional, Jones, Sarah, additional, Solorzano, Guillermo, additional, Elliott, Matthew, additional, Burns, Ted, additional, Crowell, Allison, additional, Eggleston, Deborah, additional, Wagoner, Mary, additional, Shaibani, Aziz, additional, Oates, Chantae, additional, Machado, Pedro, additional, Hanna, Michael, additional, Greensmith, Linda, additional, Ahmed, Mhoriam, additional, Vivekanandam, Vinojini, additional, Appleby, Matthew, additional, Ransley, George, additional, Eshun, Edwin Eshun, additional, Skorupinska, Iwona, additional, Germain, Louise, additional, Laxa, Ana Marie, additional, Pontes, Joana Roca, additional, Bellin, Anna, additional, and Anifowoshe, Dolapo, additional

Published
2023
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41. Autosomal dominant in cis D4Z4 repeat array duplication alleles in facioscapulohumeral dystrophy

Author

Lemmers, Richard J L F, primary, Butterfield, Russell, additional, van der Vliet, Patrick J, additional, de Bleecker, Jan L, additional, van der Pol, Ludo, additional, Dunn, Diane M, additional, Erasmus, Corrie E, additional, D'Hooghe, Marc, additional, Verhoeven, Kristof, additional, Balog, Judit, additional, Bigot, Anne, additional, van Engelen, Baziel, additional, Statland, Jeffrey, additional, Bugiardini, Enrico, additional, van der Stoep, Nienke, additional, Evangelista, Teresinha, additional, Marini-Bettolo, Chiara, additional, van den Bergh, Peter, additional, Tawil, Rabi, additional, Voermans, Nicol C, additional, Vissing, John, additional, Weiss, Robert B, additional, and van der Maarel, Silvère M, additional

Published
2023
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42. List of contributors

Author

Artukoglu, Bekir B., primary, Bachoo, Robert M., additional, Baranzini, Sergio E., additional, Benson, Merrill D., additional, Biglan, Kevin, additional, Blakeney, Iona, additional, Bloch, Michael H., additional, Brady, Melanie, additional, Brandsema, John F., additional, Broccolini, Aldobrando, additional, Brown, Robert H., additional, Cohen, Bernard, additional, Cole, Jordan J., additional, Comi, Anne M., additional, Crabbe, John C., additional, Darras, Basil T., additional, Dowling, Michael M., additional, Dunn, Walter, additional, Elroy-Stein, Orna, additional, Elsheikh, Bakri H., additional, Engel, Andrew G., additional, Fahn, Stanley, additional, Fasching, Liana, additional, Fears, Scott C., additional, Felling, Ryan J., additional, Ferner, Rosalie E., additional, Fink, John K., additional, Gillespie, Charles F., additional, Goldman, Alica M., additional, Goldman, Jill, additional, Gutmann, David H., additional, Haltia, Matti, additional, Hauser, Stephen L., additional, Hilbert, James E., additional, Iliopoulos, Othon, additional, Islam, Monica P., additional, Jenkins, Aaron K., additional, Jia, Xiaoming, additional, Jungbluth, Heinz, additional, Kayani, Saima N., additional, Khemani, Pravin, additional, Kirkham, Fenella J., additional, Kirkorian, A. Yasmine, additional, Kissel, John T., additional, Klein, Christine, additional, Kleopa, Kleopas A., additional, Kolb, Stephen J., additional, Konstantakou, Eumorphia, additional, Lambracht-Washington, Doris, additional, Lennington, Jessica B., additional, Lewis, David A., additional, Liang, Wen-Chen, additional, Lidstone, Paven A., additional, Lohmann, Katja, additional, Lombroso, Paul J., additional, Maher, Elizabeth A., additional, Marshall, Frederick, additional, McCann, Meghan, additional, McGarry, Andrew, additional, Meola, Giovanni, additional, Metelo, Ana, additional, Miller, Bruce L., additional, Mirabella, Massimiliano, additional, Mizutani, Shuki, additional, Mole, Sara E., additional, Moxley, Richard T., additional, Muntoni, Francesco, additional, Nemeroff, Charles B., additional, Nishino, Ichizo, additional, Noebels, Jeffrey L., additional, Pandolfo, Massimo, additional, Pevsner, Jonathan, additional, Ptáček, Louis, additional, Ralph, Jeffrey, additional, Renthal, William, additional, Reus, Victor I., additional, Roach, E. Steve, additional, Rosenberg, Roger N., additional, Savarese, Antonia M., additional, Sawyer, Russell P., additional, Scherer, Steven S., additional, Schiffmann, Raphael, additional, Schulz, Angela, additional, Sewry, Caroline, additional, Shakkottai, Vikram G., additional, Shinagawa, Shunichiro, additional, Singh, Pratibha, additional, Sreedharan, Jemeen, additional, Statland, Jeffrey M., additional, Szabo, Steven T., additional, Szuhay, Gabor, additional, Udd, Bjarne, additional, Vaccarino, Flora M., additional, Volk, David W., additional, Wilson, Kathleen S., additional, Xia, Weiming, additional, and Yu, Gang, additional

Published
2020
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44. The amyotrophic lateral sclerosis-health index (ALS-HI): development and evaluation of a novel outcome measure

Author

Varma, Anika, Weinstein, Jennifer, Seabury, Jamison, Rosero, Spencer, Zizzi, Christine, Alexandrou, Danae, Wagner, Ellen, Dilek, Nuran, Heatwole, John, Wuu, Joanne, Caress, James, Bedlack, Richard, Granit, Volkan, Statland, Jeffrey, Mehta, Paul, Benatar, Michael, Kaat, Aaron, and Heatwole, Chad

Subjects
Neurology, Neurology (clinical)
Abstract

Objective: The identification of effective therapeutics for ALS necessitates valid and responsive outcome measures to track disease progression and therapeutic gain in clinical trial settings. The Amyotrophic Lateral Sclerosis-Health Index (ALS-HI) is a multifaceted, disease-specific patient-reported outcome measure (PRO) designed to measure ALS symptomatic disease burden in adults with ALS. Methods: Through a national cross-sectional study of individuals with ALS, we identified the most important symptoms in ALS. These symptoms were incorporated into the ALS-HI, a measure that quantifies the multifaceted disease burden in ALS. We performed factor analysis, qualitative patient interviews, test-retest reliability assessment, and known groups analysis to evaluate and validate the ALS-HI. Results: The cross-sectional study included 497 participants with ALS who identified the most important symptoms to include in the ALS-HI. Fifteen participants beta tested the ALS-HI and found it to be clear, easy to use, and relevant. Twenty-one participants engaged in a test-retest reliability study, which indicated the reliability of the instrument (intraclass correlation coefficient = 0.952 for full instrument). The final ALS-HI and its subscales demonstrated a high internal consistency (Cronbach’s α = 0.981 for full instrument) and an ability to differentiate between groups with dissimilar disease severity. Conclusions: This research supports use of the ALS-HI as a valid, sensitive, reliable, and relevant PRO to assess the multifactorial disease burden faced by adults with ALS. The ALS-HI has potential as a mechanism to track disease progression and treatment efficacy during therapeutic trials.

Published
2023

45. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

Author

Logullo, Francesco O., Simone, Isabella, Logroscino, Giancarlo, Salvi, Fabrizio, Bartolomei, Ilaria, Borghero, Giuseppe, Murru, Maria Rita, Costantino, Emanuela, Pani, Carla, Puddu, Roberta, Caredda, Carla, Piras, Valeria, Tranquilli, Stefania, Cuccu, Stefania, Corongiu, Daniela, Melis, Maurizio, Milia, Antonio, Marrosu, Francesco, Marrosu, Maria Giovanna, Floris, Gianluca, Cannas, Antonino, Capasso, Margherita, Caponnetto, Claudia, Mancardi, Gianluigi, Origone, Paola, Mandich, Paola, Conforti, Francesca L., Cavallaro, Sebastiano, Mora, Gabriele, Marinou, Kalliopi, Sideri, Riccardo, Penco, Silvana, Mosca, Lorena, Lunetta, Christian, Pinter, Giuseppe Lauria, Corbo, Massimo, Riva, Nilo, Carrera, Paola, Volanti, Paolo, Mandrioli, Jessica, Fini, Nicola, Fasano, Antonio, Tremolizzo, Lucio, Arosio, Alessandro, Ferrarese, Carlo, Trojsi, Francesca, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Piccirillo, Giovanni, Femiano, Cinzia, Ticca, Anna, Ortu, Enzo, La Bella, Vincenzo, Spataro, Rossella, Colletti, Tiziana, Sabatelli, Mario, Zollino, Marcella, Conte, Amelia, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Santarelli, Marialuisa, Petrucci, Antonio, Pugliatti, Maura, Pirisi, Angelo, Parish, Leslie D., Occhineri, Patrizia, Giannini, Fabio, Battistini, Stefania, Ricci, Claudia, Benigni, Michele, Cau, Tea B., Loi, Daniela, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Barberis, Marco, Restagno, Gabriella, Casale, Federico, Marrali, Giuseppe, Fuda, Giuseppe, Ossola, Irene, Cammarosano, Stefania, Canosa, Antonio, Ilardi, Antonio, Manera, Umberto, Grassano, Maurizio, Tanel, Raffaella, Pisano, Fabrizio, Harms, Matthew B., Goldstein, David B., Shneider, Neil A., Goutman, Stephen, Simmons, Zachary, Miller, Timothy M., Chandran, Siddharthan, Pal, Suvankar, Manousakis, Georgios, Appel, Stanley H., Simpson, Ericka, Wang, Leo, Baloh, Robert H., Gibson, Summer, Bedlack, Richard, Lacomis, David, Sareen, Dhruv, Sherman, Alexander, Bruijn, Lucie, Penny, Michelle, Allen, Andrew S., Appel, Stanley, Bedlack, Richard S., Boone, Braden E., Brown, Robert, Carulli, John P., Chesi, Alessandra, Chung, Wendy K., Cirulli, Elizabeth T., Cooper, Gregory M., Couthouis, Julien, Day-Williams, Aaron G., Dion, Patrick A., Gitler, Aaron D., Glass, Jonathan D., Han, Yujun, Harris, Tim, Hayes, Sebastian D., Jones, Angela L., Keebler, Jonathan, Krueger, Brian J., Lasseigne, Brittany N., Levy, Shawn E., Lu, Yi-Fan, Maniatis, Tom, McKenna-Yasek, Diane, Myers, Richard M., Petrovski, Slavé, Pulst, Stefan M., Raphael, Alya R., Ravits, John M., Ren, Zhong, Rouleau, Guy A., Sapp, Peter C., Sims, Katherine B., Staropoli, John F., Waite, Lindsay L., Wang, Quanli, Wimbish, Jack R., Xin, Winnie W., Phatnani, Hemali, Kwan, Justin, Broach, James R., Arcila-Londono, Ximena, Lee, Edward B., Van Deerlin, Vivianna M., Fraenkel, Ernest, Ostrow, Lyle W., Baas, Frank, Zaitlen, Noah, Berry, James D., Malaspina, Andrea, Fratta, Pietro, Cox, Gregory A., Thompson, Leslie M., Finkbeiner, Steve, Dardiotis, Efthimios, Hornstein, Eran, MacGowan, Daniel J., Heiman-Patterson, Terry, Hammell, Molly G., Patsopoulos, Nikolaos A., Dubnau, Joshua, Nath, Avindra, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia, LeNail, Alexander, Lima, Leandro, Rothstein, Jeffrey D., Svendsen, Clive N., Van Eyk, Jenny, Maragakis, Nicholas J., Kolb, Stephen J., Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J. Paul, Wu, Gang, Rampersaud, Evadnie, Wuu, Joanne, Rademakers, Rosa, Züchner, Stephan, Schule, Rebecca, McCauley, Jacob, Hussain, Sumaira, Cooley, Anne, Wallace, Marielle, Clayman, Christine, Barohn, Richard, Statland, Jeffrey, Ravits, John, Swenson, Andrea, Jackson, Carlayne, Trivedi, Jaya, Khan, Shaida, Katz, Jonathan, Jenkins, Liberty, Burns, Ted, Gwathmey, Kelly, Caress, James, McMillan, Corey, Elman, Lauren, Pioro, Erik, Heckmann, Jeannine, So, Yuen, Walk, David, Maiser, Samuel, Zhang, Jinghui, Silani, Vincenzo, Ticozzi, Nicola, Gellera, Cinzia, Ratti, Antonia, Taroni, Franco, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P., Sorarù, Gianni, Cereda, Cristina, D’Alfonso, Sandra, Corrado, Lucia, De Marchi, Fabiola, Corti, Stefania, Ceroni, Mauro, Mazzini, Letizia, Siciliano, Gabriele, Filosto, Massimiliano, Inghilleri, Maurizio, Peverelli, Silvia, Colombrita, Claudia, Poletti, Barbara, Maderna, Luca, Del Bo, Roberto, Gagliardi, Stella, Querin, Giorgia, Bertolin, Cinzia, Pensato, Viviana, Castellotti, Barbara, Camu, William, Mouzat, Kevin, Lumbroso, Serge, Corcia, Philippe, Meininger, Vincent, Besson, Gérard, Lagrange, Emmeline, Clavelou, Pierre, Guy, Nathalie, Couratier, Philippe, Vourch, Patrick, Danel, Véronique, Bernard, Emilien, Lemasson, Gwendal, Al Kheifat, Ahmad, Al-Chalabi, Ammar, Andersen, Peter, Basak, A. Nazli, Blair, Ian P., Chio, Adriano, Cooper-Knock, Jonathan, de Carvalho, Mamede, Dekker, Annelot, Drory, Vivian, Redondo, Alberto Garcia, Gotkine, Marc, Hardiman, Orla, Hide, Winston, Iacoangeli, Alfredo, Glass, Jonathan, Kenna, Kevin, Kiernan, Matthew, Kooyman, Maarten, Landers, John, McLaughlin, Russell, Middelkoop, Bas, Mill, Jonathan, Neto, Miguel Mitne, Moisse, Mattieu, Pardina, Jesus Mora, Morrison, Karen, Newhouse, Stephen, Pinto, Susana, Pulit, Sara, Robberecht, Wim, Shatunov, Aleksey, Shaw, Pamela, Shaw, Chris, Sproviero, William, Tazelaar, Gijs, van Damme, Philip, van den Berg, Leonard, van der Spek, Rick, van Eijk, Kristel, van Es, Michael, van Rheenen, Wouter, van Vugt, Joke, Veldink, Jan, Weber, Markus, Williams, Kelly L., Zatz, Mayana, Bauer, Denis C., Twine, Natalie A., Nicolas, Aude, Kenna, Kevin P., Renton, Alan E., Faghri, Faraz, Chia, Ruth, Dominov, Janice A., Kenna, Brendan J., Nalls, Mike A., Keagle, Pamela, Rivera, Alberto M., Murphy, Natalie A., van Vugt, Joke J.F.A., Geiger, Joshua T., Van der Spek, Rick A., Pliner, Hannah A., Shankaracharya, Smith, Bradley N., Topp, Simon D., Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D., Kenna, Aoife, Messina, Sonia, Simone, Isabella L., Ferrucci, Luigi, Moreno, Cristiane de Araujo Martins, Kamalakaran, Sitharthan, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C., Wyman, Stacia K., LeNail, Alex, Van Eyk, Jennifer E., Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W., Sidle, Katie C., Hardy, John, Singleton, Andrew B., Johnson, Janel O., Arepalli, Sampath, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, ten Asbroek, Anneloor L.M.A., Muñoz-Blanco, José Luis, Hernandez, Dena G., Ding, Jinhui, Gibbs, J. Raphael, Scholz, Sonja W., Floeter, Mary Kay, Campbell, Roy H., Landi, Francesco, Bowser, Robert, MacGowan, Daniel J.L., Kirby, Janine, Pioro, Erik P., Pamphlett, Roger, Broach, James, Gerhard, Glenn, Dunckley, Travis L., Brady, Christopher B., Kowall, Neil W., Troncoso, Juan C., Le Ber, Isabelle, Heiman-Patterson, Terry D., Kamel, Freya, Van Den Bosch, Ludo, Strom, Tim M., Meitinger, Thomas, Van Eijk, Kristel R., Moisse, Matthieu, McLaughlin, Russell L., Van Es, Michael A., Boylan, Kevin B., Van Blitterswijk, Marka, Morrison, Karen E., Mora, Jesús S., Drory, Vivian E., Shaw, Pamela J., Turner, Martin R., Talbot, Kevin, Fifita, Jennifer A., Nicholson, Garth A., Esteban-Pérez, Jesús, García-Redondo, Alberto, Rogaeva, Ekaterina, Zinman, Lorne, Cooper-Knock, Johnathan, Brice, Alexis, Goutman, Stephen A., Feldman, Eva L., Gibson, Summer B., Van Damme, Philip, Ludolph, Albert C., Andersen, Peter M., Weishaupt, Jochen H., Trojanowski, John Q., Brown, Robert H., Jr., van den Berg, Leonard H., Veldink, Jan H., Stone, David J., Tienari, Pentti, Chiò, Adriano, Shaw, Christopher E., Traynor, Bryan J., and Landers, John E.

Published
2018
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46. Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis

Author

Placek, Katerina, Benatar, Michael, Wuu, Joanne, Rampersaud, Evadnie, Hennessy, Laura, Van Deerlin, Vivianna M, Grossman, Murray, Irwin, David J, Elman, Lauren, McCluskey, Leo, Quinn, Colin, Granit, Volkan, Statland, Jeffrey M, Burns, Ted M, Ravits, John, Swenson, Andrea, Katz, Jon, Pioro, Erik P, Jackson, Carlayne, Caress, James, So, Yuen, Maiser, Samuel, Walk, David, Lee, Edward B, Trojanowski, John Q, Cook, Philip, Gee, James, Sha, Jin, Naj, Adam C, Rademakers, Rosa, Chen, Wenan, Wu, Gang, Paul Taylor, J, and McMillan, Corey T

Published
2021
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48. Autosomal dominant in cis D4Z4 repeat array duplication alleles in facioscapulohumeral dystrophy.

Author

Lemmers, Richard J L F, Butterfield, Russell, Vliet, Patrick J van der, Bleecker, Jan L de, van der Pol, Ludo, Dunn, Diane M, Erasmus, Corrie E, D'Hooghe, Marc, Verhoeven, Kristof, Balog, Judit, Bigot, Anne, Engelen, Baziel van, Statland, Jeffrey, Bugiardini, Enrico, van der Stoep, Nienke, Evangelista, Teresinha, Marini-Bettolo, Chiara, van den Bergh, Peter, Tawil, Rabi, and Voermans, Nicol C

Subjects
FACIOSCAPULOHUMERAL muscular dystrophy, ALLELES, SOUTHERN blot, DYSTROPHY, ALLELES in plants, TRANSCRIPTION factors, SKELETAL muscle, CHROMOSOME duplication
Abstract

Facioscapulohumeral dystrophy (FSHD) has a unique genetic aetiology resulting in partial chromatin relaxation of the D4Z4 macrosatellite repeat array on 4qter. This D4Z4 chromatin relaxation facilitates inappropriate expression of the transcription factor DUX4 in skeletal muscle. DUX4 is encoded by a retrogene that is embedded within the distal region of the D4Z4 repeat array. In the European population, the D4Z4 repeat array is usually organized in a single array that ranges between 8 and 100 units. D4Z4 chromatin relaxation and DUX4 derepression in FSHD is most often caused by repeat array contraction to 1–10 units (FSHD1) or by a digenic mechanism requiring pathogenic variants in a D4Z4 chromatin repressor like SMCHD1, combined with a repeat array between 8 and 20 units (FSHD2). With a prevalence of 1.5% in the European population, in cis duplications of the D4Z4 repeat array, where two adjacent D4Z4 arrays are interrupted by a spacer sequence, are relatively common but their relationship to FSHD is not well understood. In cis duplication alleles were shown to be pathogenic in FSHD2 patients; however, there is inconsistent evidence for the necessity of an SMCHD1 mutation for disease development. To explore the pathogenic nature of these alleles we compared in cis duplication alleles in FSHD patients with or without pathogenic SMCHD1 variant. For both groups we showed duplication-allele-specific DUX4 expression. We studied these alleles in detail using pulsed-field gel electrophoresis-based Southern blotting and molecular combing, emphasizing the challenges in the characterization of these rearrangements. Nanopore sequencing was instrumental to study the composition and methylation of the duplicated D4Z4 repeat arrays and to identify the breakpoints and the spacer sequence between the arrays. By comparing the composition of the D4Z4 repeat array of in cis duplication alleles in both groups, we found that specific combinations of proximal and distal repeat array sizes determine their pathogenicity. Supported by our algorithm to predict pathogenicity, diagnostic laboratories should now be furnished to accurately interpret these in cis D4Z4 repeat array duplications, alleles that can easily be missed in routine settings. [ABSTRACT FROM AUTHOR]

Published
2024
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