METABOLIC DISSERTATION The pathogenomics of McArdle disease—genes, enzymes, models, and therapeutic implications Gisela Nogales-Gadea & Alfredo Santalla & Astrid Brull & Noemi de Luna & Alejandro Lucía & Tomàs Pinós Received: 11 April 2014 /Revised: 17 June 2014 /Accepted: 25 June 2014 # SSIEM 2014 Abstract Numerous biomedical advances have been made since Carl and Gerty Cori discovered the enzyme phosphorylase in the 1940s and the Scottish physician Brian McArdle reported in 1951 a previously ‘undescribed disorder characterized by a gross failure of the breakdown in muscle of glycogen’. Today we know that this disorder, commonly known as ‘McArdle disease’, is caused by inherited deficiency of the muscle isoform of glycogen phosphorylase (GP). Here we review the main aspects of the ‘pathogenomics’ of this disease including, among others: the spectrum of mutations in the gene (PYGM) encoding muscle GP; the interplay between the different tissue GP isoforms in cellular cultures and in patients; what can we learn from naturally occurring and recently laboratory-generated animal models of the disease; and potential therapies. Introduction Glycogenosis type V (glycogen storage disease type V [GSD V], McArdle disease or myophosphorylase deficiency; OMIM® database number 232600) is a disorder of skeletal- muscle carbohydrate metabolism originally described in 1951 (McArdle 1951). It is one of the most frequent genetic myop- athies, e.g., with a prevalence of ∼1/167,000 in Spain, with both sexes similarly affected (Lucia et al 2012). This disorder is caused by pathogenic mutations in both copies of the gene ( PYGM) encoding the muscle isoform of glycogen phosphorylase (hereafter abbreviated as GP), also known as myophosphorylase (Lucia et al 2008). Starting with a summa- ry of the main phenotype consequences of the disease, here we review the genotype characteristics of the disease as well as available and potential therapy strategies. Main phenotype consequences are confined to the skeletal muscle — exercise intolerance The muscle isoform of GP (GP-MM; EC 2.4.1.1) catalyzes and regulates the breakdown of glycogen into glucose-1- phosphate in muscle fibers (by removing α-1,4 glucosyl units from the outer glycogen branches). Thus, patients are unable to obtain energy from their muscle glycogen stores and, as a result, commonly experience exercise intolerance. The latter typically consists of acute crises of early fatigue and muscle stiffness and contractures, especially at the start of exercise, that usually disappear if exercise is stopped or intensity is Gisela Nogales-Gadea Communicated by: Bruce A. Barshop G. Nogales-Gadea (*) Neuromuscular Diseases Unit, Institut de Recerca del Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Av. Maria Claret 167, 08025 Barcelona, Spain e-mail: gnogalga7@gmail.com G. Nogales-Gadea Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands A. Brull : N. de Luna : T. Pinós Departament de Patologia Mitocondrial i Neuromuscular, Hospital Universitari Vall d’Hebron, Institut de Recerca (VHIR), Universitat Autónoma de Barcelona, Barcelona, Spain A. Santalla Universidad Pablo de Olavide, Sevilla, Spain A. Santalla : A. Lucía Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain A. Lucía Universidad Europea, Madrid, Spain A. Brull : N. de Luna : T. Pinós Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain J Inherit Metab Dis DOI 10.1007/s10545-014-9743-2