A DM1 family with interruptions associated with atypical symptoms and late onset but not with a milder phenotype

Ballester‐Lopez, A. et al. (2020) A DM1 family with interruptions associated with atypical symptoms and late onset but not with a milder phenotype. Human Mutation, 41(2), pp. 420-431. (doi: 10.1002/humu.23932) (PMID:31608518)

Abstract

Carriage of interruptions in CTG repeats of the myotonic dystrophy protein kinase gene has been associated with a broad spectrum of myotonic dystrophy type 1 (DM1) phenotypes, mostly mild. However, the data available on interrupted DM1 patients and their phenotype are scarce. We studied 49 Spanish DM1 patients, whose clinical phenotype was evaluated in depth. Blood DNA was obtained and analyzed through triplet‐primed polymerase chain reaction (PCR), long PCR‐Southern blot, small pool PCR, AciI digestion, and sequencing. Five patients of our registry (10%), belonging to the same family, carried CCG interruptions at the 3’ end of the CTG expansion. Some of them presented atypical traits such as a very late onset of symptoms (>50 years) and a severe axial and proximal weakness requiring walking assistance. They also showed classic DM1 symptoms including cardiac and respiratory dysfunction, which were severe in some of them. Sizes and interrupted allele patterns were determined, and we found a contraction and an expansion in two intergenerational transmissions. Our study contributes to the observation that DM1 patients carrying interruptions present with atypical clinical features that can make DM1 diagnosis difficult, with a later than expected age of onset and a previously unreported aging‐related severe disease manifestation.

• Item Type: Articles
• Additional Information: The research of Gisela Nogales-Gadea and Alejandro Lucia is funded by Instituto de Salud Carlos III (grant numbers PI15/01756, PI15/00558 and PI18/00713) and co-financed by Fondos FEDER. Gisela Nogales-Gadea is supported by a Miguel Servet research contract (ISCIII CD14/00032, ISCIII CPII19/00021 and FEDER) and by a Trampoline Grant #21108 from AMF Telethon. Alfonsina BallesterLopez is funded by an FI Agaur fellowship ref. FI_B 01090. Emma Koehorst is funded by the “La Caixa” Foundation (ID 100010434), fellowship code LCF/BQ/IN18/11660019, cofunded by the European Union´s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant THIS ARTICLE IS PROTECTED BY COPYRIGHT. ALL RIGHTS RESERVED. Accepted Article agreement nº713673. Ian Linares-Pardo is funded by CP14/00032. Judit NúñezManchón is funded by AFM Telethon Trampoline Grant #21108. Giuseppe Lucente is supported by a Rio Hortega contract (ISCIII CM16/00016 and FEDER). Darren Monckton, Gayle Overend and Sarah Cumming received funding from the Myotonic Dystrophy Support Group (UK).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Monckton, Professor Darren and Cumming, Dr Sarah and Overend, Dr Gayle
• Authors: Ballester‐Lopez, A., Koehorst, E., Almendrote, M., Martínez‐Piñeiro, A., Lucente, G., Linares‐Pardo, I., Núñez‐Manchón, J., Guanyabens, N., Cano, A., Lucia, A., Overend, G., Cumming, S. A., Monckton, D. G., Casadevall, T., Isern, I., Sánchez‐Ojanguren, J., Planas, A., Rodríguez‐Palmero, A., Monlleó‐Neila, L., Pintos‐Morell, G., Ramos‐Fransi, A., Coll‐Cantí, J., and Nogales‐Gadea, G.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Human Mutation
• Publisher: Wiley
• ISSN: 1059-7794
• ISSN (Online): 1098-1004
• Published Online: 14 October 2019
• Copyright Holders: Copyright © 2019 Wiley Periodicals, Inc.
• First Published: First published in Human Mutation 41(2):420-431
• Publisher Policy: Reproduced in accordance with the publisher copyright policy