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The relationship between deficit in digit span and genotype in nonsense mutation Duchenne muscular dystrophy

2018; Lippincott Williams & Wilkins; Volume: 91; Issue: 13 Linguagem: Inglês

10.1212/wnl.0000000000006245

1526-632X

Mathula Thangarajh, Gary Elfring, Panayiota Trifillis, Joseph McIntosh, Stuart W. Peltz, Monique M. Ryan, Andrew J. Kornberg, Victoria Rodriguez‐Casero, Alison Wray, Kristi Jones, Kathryn N. North, Nathalie Goemans, Gunnar Buyse, Craig Campbell, Jean K. Mah, Harvey B. Sarnat, Kathryn Selby, Thomas Voït, Valérie Doppler, Denis De Castro, B. Chabrol, Nicolas Lévy, C. Halbert, Yann Péréon, Armelle Magot, Julie Perrier, Jean-Yves Mahe, Ulrike Schara, Soren Lutz, Melanie Busse, Adela Della Marina, Janbernd Kirschner, Angela Stanescu, Annette Pohl, Cornelia RensingZimmerman, Enrico Bertini, Adele D’Amico, Annamaria Kofler, Adelina Carlesi, Anna Maria Bonetti, Luigino Santecchia, Francesco Emma, Gianluca Bergami, Eugenio Mercuri, Gessica Vasco, Flaviana Bianco, Elena Mazzone, Roberto De Sanctis, Paolo Alfieri, Marika Pane, Sonia Messina, Giacomo P. Comi, Francesca Magri, Valeria Lucchini, Stefania Corti, Maurizio Moggio, Monica Sciacco, Nereo Bresolin, A. Prelle, Roberta Magri, Roberta Virgilio, C. Lamperti, Yoram Nevo, Taia DorWollman, Juan J. Vílchez, Nuria Muelas, Teresa Sevilla, Patricia Smeyers, Alberto De La Osa, Jaume Colomer, C. Ortez, A. Nascimento, Ana Febrer, Julita Medina, M. Tulinus, brynja Thorarinsdottir, Niklas Darín, Thomas Sejersen, M. Hovmöller, K. Bushby, Volker Straub, Michela Guglieri, Anna Sárközy, Tracey Willis, Michelle Eagle, Anna Mayhew, Francesco Muntoni, Sebahattin Çirak, Adnan Y. Manzur, S. Robb, Maria Kinali, Rosaline Christina Mary Quinlivan, Martin Richard Smith, Rajesh K. Pandey, Brenda Wong, James J. Collins, Richard S. Finkel, Cartsen Bonnemann, Michele Yang, A. Reghan Foley, Sabrina W. Yum, Jacinda B. Sampson, Mark B. Bromberg, Kathryn J. Swoboda, John Day, Peter Karachunski, Katherine D. Mathews, Daniel J. Bonthius, Karla S. Laubenthal, Basil T. Darras, Peter B. Kang, Julie Parson, Richard J. Barohn, Majed Dasouki, Heather J. Anderson, Jeffrey M. Burns, Mazen M. Dimachkie, Mamatha Pasnoor, Yunxia Wang, Emma Ciafaloni, Chad Heatwole, Anne M. Connolly, Alan Pestronk, Muhammad Al‐Lozi, Glenn Lopate, Paul T. Golumbek, Brian Sommerville, Leo H. Wang, Anna Wojcicka-Mitchell, Andrew Godbey, Matthew B. Harms, Arun Varadachary, Stanley Iyadurai, Luisa Rojas, S. Iannacone, Chaiyos Khonghatithum, Douglas M. Sproule, Darryl C. De Vivo, Andre Constantinescu, Craig M. McDonald, Jay J. Han, Ben Renfroe, Barry S. Russman, Michael D. Sussman, Stephanie Burns Wechsler, Vern C. Juel, Lisa D. Hobson‐Webb, Edward A. Smith,

Genetic Neurodegenerative Diseases

Objective To evaluate the relationship between deficit in digit span and genotype in nonsense mutation (nm) Duchenne muscular dystrophy (DMD) (nmDMD). Methods We investigated the relationship between normalized digit-span forward (d-sf) and digit-span backward (d-sb) scores to the location of nmDMD mutations in 169 participants ≥5 to ≤20 years who participated in a phase 2b clinical trial. Because alternative promoters are found upstream of DMD exons 30, 45, and 63, we correlated d-sf and d-sb to the specific nmDMD mutation location. Results Participants with nm downstream of exon 30, downstream of exon 45, and downstream of exon 63 had significantly lower normalized d-sf scores ( p < 0.0001). Participants with nm downstream of exon 45 in addition had significantly lower normalized d-sb score ( p < 0.04). There was no significant difference in the normalized d-sb score in participants with mutations upstream or downstream of DMD exon 30 or upstream or downstream of DMD exon 63. Conclusion Our data provide evidence that specific cognitive deficits correlate to genotype in individuals with nmDMD, highlighting the critical role of brain-specific dystrophin isoforms in the neurobiological manifestations of this disease. Clinicaltrials.gov identifier NCT02090959.