Abstract
McArdle disease is an autosomal recessive condition caused by deficiency of the PYGM gene-encoded muscle isoform of glycogen phosphorylase. Some cases of “manifesting” heterozygotes or carriers (i.e., patients who show some McArdle-like symptoms or signs despite being carriers of only one mutated PYGM allele) have been reported in the literature but there is controversy, with misdiagnosis being a possibility. The purpose of our study was to determine if there are actually “manifesting” heterozygotes of McArdle disease and, if existing, whether statin treatment can trigger such condition. Eighty-one relatives of McArdle patients (among a total of 16 different families) were studied. We determined whether they were carriers of PYGM mutations and also collected information on exercise tests (second wind and modified Wingate anaerobic test) and statin intake. We found 50 carriers and 31 non-carriers of PYGM mutations. Although we found existence of heterozygotes manifesting some exercise-related muscle problems such as exacerbated myalgia or weakness, they only accounted for 14% of the carriers and muscle symptoms were milder than those commonly reported in patients. Further, no carrier (whether reporting symptoms or not) showed the second wind phenomenon or a flat blood lactate response to maximal-intensity exercise, both of which are hallmarks of McArdle disease. On the other hand, statin myotoxicity was not associated with muscle symptom onset.
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20 July 2018
Unfortunately the name of one of the authors was spelled incorrectly in the published original article. The correct name is Alejandro Santos-Lozano. The original article got updated.
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Acknowledgements
We are grateful to the strong commitment and the helpful participation of the members of the Spanish Association of Glycogenosis in Spain.
Funding
This study was funded by Fondo de Investigaciones Sanitarias and FEDER funds from the European Union (A.L., PI15/00558; G.N.G, PI15/01756 and CP14/00032, J.A. PI14/00903), AFM Telethon Trampoline Grant No. 21108, the Biomedical Research Networking Center on Frailty and Healthy Aging (CIBERFES groups CB16/10/00477 and CB16/10/00314). J.N.M is funded by AFM Telethon Trampoline Grant No. 21108. A.B.L is funded by an FI Agaur fellowship FI_B 01090. E.K is funded by PI15/01756. I.L.P is funded by CP14/00032. C.R.L is funded by a FPI Grant No. BES-2016-077199. G.N.G is supported by a Miguel Servet research contract (ISCIII CD14/00032 and FEDER).
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Judit Núñez-Manchón declares that she is supported by a contract in the project AFM Telethon #21108. Alfonsina Ballester-Lopez declares funding by an FI Agaur fellowship FI_B 01090. Emma Koehorst declares that she is supported by a contract in the project PI15/01756 from Instituto de Salud Carlos III cofinanced by FEDER. Ian Linares-Pardo declares that he has a contract in the Miguel Servet project CP14/00032 cofinanced by FEDER. Daniëlle Coenen, Ignacio Ara, Alba Ramos-Fransi, Alicia Martinez Piñeiro, Miriam Almendrote, Jaume Coll, Alejandro Santos Lozano, Mauricio de Castro, and Alfredo Santalla declare that they have no conflict of interest. Carlos Rodriguez-Lopez declares funding by Secretaría de Estado de Investigación, Desarrollo e Innovación fellowship BES-2016-077199. Giuseppe Lucente declares that he is supported by a Rio Hortega contract (ISCIII CM16/00016 and FEDER). Guillem Pintos-Morell declares that he had had personal fees from Shire, and from BioMarin, outside the submitted work. Joaquin Arenas declares that he has a grant of the Instituto de Salud Carlos III and FEDER. Miguel Angel Martín declares that he has a grant of the Instituto de Salud Carlos III and FEDER. Alejandro Lucia declares that he has a grant of the Instituto de Salud Carlos III and FEDER. Gisela Nogales-Gadea declares grants from, Madrid, Spain (CP14/00032, PI15/01756 and FEDER) and France, AMF Telethon Trampoline Grant No. 21108.
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All procedures followed were in accordance with the ethical standards of the responsible committee of the University Hospital Germans Trias i Pujol (study reviewed and approved by this committee with ref. PI-18-027) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.
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This article does not contain any studies with animal subjects performed by the any of the authors.
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Communicating Editor: Terry G.J. Derks
The original version of this article was revised: cause the name Alejandro Santos-Lazano was incorrect.
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Núñez-Manchón, J., Ballester-Lopez, A., Koehorst, E. et al. Manifesting heterozygotes in McArdle disease: a myth or a reality—role of statins. J Inherit Metab Dis 41, 1027–1035 (2018). https://doi.org/10.1007/s10545-018-0203-2
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DOI: https://doi.org/10.1007/s10545-018-0203-2