The relationship between deficit in digit span and genotype in nonsense mutation Duchenne muscular dystrophy
Mathula Thangarajh, Gary L Elfring, Panayiota Trifillis, Joseph McIntosh, Stuart W Peltz, Ataluren Phase 2b Study Group, Monique M Ryan, Andrew J Kornberg, Victoria RodriguezCasero, Alison Wray, Kristi J Jones, Kathryn North, Nathalie Goemans, Gunnar Marceo Buyse, Craig Campbell, Jean Mah, Harvey Sarnat, Kathryn Selby, Thomas Voit, Valerie Doppler, Denis De Castro, Brigitte Chabrol, Nicolas Levy, Cecile Halbert, Yann Pereon, 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 Maria Mercuri, Gessica Vasco, Flaviana Bianco, Elena Stacy Mazzone, Roberto De Sanctis, Paolo Alfieri, Marika Pane, Sonia Messina, Giacomo Pietro Comi, Francesca Magri, Valeria Lucchini, Stefania Paola Corti, Maurizio Gualtiero Moggio, Monica Sciacco, Nereo Bresolin, Alessandro Cesare Prelle, Roberta Magri, Roberta Virgilio, Costanza Lamperti, Yoram Nevo, Taia DorWollman, Juan Vilchez, Nuria Muelas, Teresa Sevilla, Patricia Smeyers, Alberto de la Osa, Jaume Colomer, Carlos Ignacio Ortez, Andres Nascimento, Ana Febrer, Julita Medina, Mar Tulinus, Brynja Thorarinsdottir, Niklas Darin, Thomas Sejersen, Mia Hovmoller, Katherine Bushby, Volker Straub, Michela Guglieri, Anna Sarkozy, Tracey Willis, Michelle Eagle, Anna Mayhew, Francesco Muntoni, Sebahattin Cirak, Adnan Yousaf Manzur, Stephanie Ann Robb, Maria Kinali, Rosaline Christina Mary Quinlivan, Martin Richard Smith, Rajesh Pandey, Brenda Wong, James Collins, Richard Finkel, Cartsen Bonnemann, Michele Yang, Aileen Reghan Foley, Sabrina Yum, Jacinda Sampson, Mark Bromberg, Kathryn Swoboda, John Day, Peter Karachunski, Katherine Mathews, Daniel Bonthius, Karla Sue Laubenthal, Basil Darras, Peter Kang, Julie Parson, Richard Barohn, Majed Dasouki, Heather Anderson, Jeffrey Burns, Mazen Dimachkie, Mamatha Pasnoor, Yunxia Wang, Emma Ciafaloni, Chad Heatwole, Anne Connolly, Alan Pestronk, Muhammad Al-Lozi, Glenn Lopate, Paul Golumbek, Brian Sommerville, Leo Wang, Anna Wojcicka-Mitchell, Andrew Godbey, Matthew Harms, Arun Varadachary, Stanley Iyadurai, Luisa Rojas, Susan Iannacone, Chaiyos Khonghatithum, Douglas Sproule, Darryl De Vivo, Andre Constantinescu, Craig McDonald, Jay Han, Ben Renfroe, Barry Russman, Michael Sussman, Stephanie BurnsWechsler, Vern Juel, Lisa Hobson-Webb, Edward Smith, Mathula Thangarajh, Gary L Elfring, Panayiota Trifillis, Joseph McIntosh, Stuart W Peltz, Ataluren Phase 2b Study Group, Monique M Ryan, Andrew J Kornberg, Victoria RodriguezCasero, Alison Wray, Kristi J Jones, Kathryn North, Nathalie Goemans, Gunnar Marceo Buyse, Craig Campbell, Jean Mah, Harvey Sarnat, Kathryn Selby, Thomas Voit, Valerie Doppler, Denis De Castro, Brigitte Chabrol, Nicolas Levy, Cecile Halbert, Yann Pereon, 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 Maria Mercuri, Gessica Vasco, Flaviana Bianco, Elena Stacy Mazzone, Roberto De Sanctis, Paolo Alfieri, Marika Pane, Sonia Messina, Giacomo Pietro Comi, Francesca Magri, Valeria Lucchini, Stefania Paola Corti, Maurizio Gualtiero Moggio, Monica Sciacco, Nereo Bresolin, Alessandro Cesare Prelle, Roberta Magri, Roberta Virgilio, Costanza Lamperti, Yoram Nevo, Taia DorWollman, Juan Vilchez, Nuria Muelas, Teresa Sevilla, Patricia Smeyers, Alberto de la Osa, Jaume Colomer, Carlos Ignacio Ortez, Andres Nascimento, Ana Febrer, Julita Medina, Mar Tulinus, Brynja Thorarinsdottir, Niklas Darin, Thomas Sejersen, Mia Hovmoller, Katherine Bushby, Volker Straub, Michela Guglieri, Anna Sarkozy, Tracey Willis, Michelle Eagle, Anna Mayhew, Francesco Muntoni, Sebahattin Cirak, Adnan Yousaf Manzur, Stephanie Ann Robb, Maria Kinali, Rosaline Christina Mary Quinlivan, Martin Richard Smith, Rajesh Pandey, Brenda Wong, James Collins, Richard Finkel, Cartsen Bonnemann, Michele Yang, Aileen Reghan Foley, Sabrina Yum, Jacinda Sampson, Mark Bromberg, Kathryn Swoboda, John Day, Peter Karachunski, Katherine Mathews, Daniel Bonthius, Karla Sue Laubenthal, Basil Darras, Peter Kang, Julie Parson, Richard Barohn, Majed Dasouki, Heather Anderson, Jeffrey Burns, Mazen Dimachkie, Mamatha Pasnoor, Yunxia Wang, Emma Ciafaloni, Chad Heatwole, Anne Connolly, Alan Pestronk, Muhammad Al-Lozi, Glenn Lopate, Paul Golumbek, Brian Sommerville, Leo Wang, Anna Wojcicka-Mitchell, Andrew Godbey, Matthew Harms, Arun Varadachary, Stanley Iyadurai, Luisa Rojas, Susan Iannacone, Chaiyos Khonghatithum, Douglas Sproule, Darryl De Vivo, Andre Constantinescu, Craig McDonald, Jay Han, Ben Renfroe, Barry Russman, Michael Sussman, Stephanie BurnsWechsler, Vern Juel, Lisa Hobson-Webb, Edward Smith
Abstract
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.
Clinicaltrialsgov identifier: NCT02090959.
© 2018 American Academy of Neurology.
Figures
Source: PubMed