Scalco et al. Orphanet J Rare Dis (2020) 15:330 https://doi.org/10.1186/s13023-020-01562-x RESEARCH Open Access Data from the European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) Renata S. Scalco1, Alejandro Lucia2,3, Alfredo Santalla3,4, Andrea Martinuzzi5, Marinela Vavla5, Gianluigi Reni5, Antonio Toscano6, Olimpia Musumeci6, Nicol C. Voermans7, Carlyn V. Kouwenberg7, Pascal Laforêt8, Beatriz San‑Millán9,10, Irene Vieitez10, Gabriele Siciliano11, Enrico Kühnle12, Rebeca Trost12, Sabrina Sacconi13, Mads G. Stemmerik14, Hacer Durmus15, Biruta Kierdaszuk16, Andrew Wakelin17, Antoni L. Andreu18, Tomàs Pinós18, Ramon Marti18, Ros Quinlivan1 and John Vissing14* on behalf of EUROMAC Consortium Abstract Background: The European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) was launched to register rare muscle glycogenoses in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases through workshops and websites. A network of twenty full and collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry. After approximately 3 years of data collection, the data in the registry was analysed. Results: Of 282 patients with confirmed diagnoses of muscle glycogenosis, 269 had McArdle disease. New phe‑ notypic features of McArdle disease were suggested, including a higher frequency (51.4%) of fixed weakness than reported before, normal CK values in a minority of patients (6.8%), ptosis in 8 patients, body mass index above background population and number of comorbidities with a higher frequency than in the background population (hypothyroidism, coronary heart disease). Conclusions: The EUROMAC project and registry have provided insight into new phenotypic features of McArdle dis‑ ease and the variety of co-comorbidities affecting people with McArdle disease. This should lead to better manage‑ ment of these disorders in the future, including controlling weight, and preventive screening for thyroid and coronary artery diseases, as well as physical examination with attention on occurrence of ptosis and fixed muscle weakness. Normal serum creatine kinase in a minority of patients stresses the need to not discard a diagnosis of McArdle disease even though creatine kinase is normal and episodes of myoglobinuria are absent. Keywords: Myopathy, Rare diseases, International registry, McArdle disease, Metabolic diseases, Glycogen storage disease Introduction Understanding rare conditions is usually based on case series or small observational studies. Thus, gaining knowledge about disease phenotypes and development *Correspondence: john.vissing@regionh.dk 14 Copenhagen Neuromuscular Center, Section 6921, Rigshospitalet, is challenging. For instance, lack of natural history data University of Copenhagen, 2100 Copenhagen, Denmark negatively impacts on identification of clinically impor- Full list of author information is available at the end of the article tant endpoints to be used in clinical trials [1]. Other © The Author(s) 2020. 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The Creative Commons Public Domain Dedication waiver (http://creat​iveco​ mmons​.org/publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Scalco et al. Orphanet J Rare Dis (2020) 15:330 Page 2 of 8 challenges include delayed diagnosis, poor subject avail- kinase and phosphoglycerate kinase deficiencies as they ability for recruitment into clinical trials and a lack of are X-linked) or for McArdle disease and phosphofruc- standardised care [1–3]. As a result, the development of tokinase deficiency, lack of enzymatic staining on mus- new pharmacological treatments for such conditions is cle biopsy. Patients with Pompe disease were excluded delayed and compromised [1, 2]. as there is a well-established registry for this disease To overcome these limitations, there are increasing already (https​://clini​caltr​ials.gov/ct2/show/NCT00​23140​ incentives to develop international registries. Registries 0). Following informed consent from the participant, data are considered key instruments for developing research were uploaded onto a safe, encrypted web-based reg- in the field of rare conditions, including glycogen storage istry. Recruited participants were able to log in, review diseases (GSDs) [4]. The EUROMAC project was funded their own information and complete selected sections by the European Union aiming to establish a network of with their personal experiences. None of the recruited clinical centres to develop the first European Registry participants or participating doctors were allowed to see for patients with McArdle Disease and very rare related data from other patients. Data entry items are shown in muscle glycogenolytic disorders presenting with activity/ Table 3 of the accompanying paper [7]. Muscle strength exercise intolerance as the key symptom [5, 6]. The pro- was assessed by manual muscle testing in patients older ject was designed and built as described in the accom- than 18 years (n = 247) by a trained neuromuscular spe- panying paper to this report [7], to raise awareness of cialist. Data was only entered once, except if missing data diagnostic accuracy of muscle GSDs, improve the care, was uploaded later. Data was based on clinical status and and collect important clinical and epidemiological data medical history at data entry. that can better describe the phenotypes and indicate end- points for use in future clinical trials. Results This paper describes the data collected in the Patient registry EUROMAC registry for patients with McArdle disease. The first patient was entered into the registry in Febru- ary 2015. Until March 2018, 313 patients from 10 coun- Methods tries were added to the registry. Thirty-one patients The registry was designed under the guidance and were excluded from data analysis due to incomplete data consensus of EUROMAC members at specific meet- entry related to diagnosis (i.e., missing muscle biopsy ings during the first months of the EUROMAC project. and/or missing genetic data). Thus, 282 participants EUROMAC members were twenty full and collaborat- were included in data analysis (Fig. 1). In this cohort, ing partners from eight European countries (Denmark, the most frequent GSD diagnosis was McArdle disease France, Germany, Greece, Italy, Spain, Turkey and United (n = 269; 95.4%). Other conditions included GSDIIIa Kingdom) and USA. The Netherlands and Poland joined (n = 2), GSDVII (n = 5), GSDIX (n = 2), GSDX (n = 1), the project later and contributed patients to the registry. The registry obtained the approval of all local Institu- tional review Boards for patient entry at the registry web- site (www.regis​tryeu​romac​.eu). The project was divided into eight work packages (WP) to develop the registry (see Table 2 in accompanying paper) [7]. The technical setup and data security for the registry are detailed in the accompanying paper [7]. After review by people affected by GSDs and by a patient representative (WP2 – AGSD-UK) to ensure clarity [8], the participant information sheet and con- sent form were translated into languages of the partici- pating countries and adapted to follow local regulations. All patients consented in writing before inclusion in the registry. Any doctor working at a European institution was able to register on the EUROMAC platform and enter patient data. Inclusion criteria were patients with a diagnosis of one of the 14 known muscle GSDs either verified by the Fig. 1 Registered patients by country. UK: United Kingdom; SP: Spain; presence of two pathogenic mutations in the relevant IT: Italy; NL: Netherlands; FR: France; DE: Germany; DK: Denmark; TR: Turkey; PL: Poland genes (one pathogenic mutation for phosphorylase b Scalco et al. Orphanet J Rare Dis (2020) 15:330 Page 3 of 8 GSDXIV (n = 1), and GSDXV (n = 2). Detailed informa- homozygous (108) or compound heterozygous (86). The tion on the 13 patients with rarer types of GSD are omit- allele frequency for the c.613G>A (p.G205S) variant was ted as the sample is too small for data analysis. Following 6.4% (homozygous in 5 and compound heterozygous a EUROMAC teaching course held in Warsaw, the first in 21), and the allele frequency for the c.2262delA was Polish patient was diagnosed with McArdle disease, and 4.3% % (homozygous in 4 and compound heterozygous entered into the registry [9]. in 13) (Table 3). All other alleles occurred at a frequency below 2%. Only five other pathogenic variants were found McArdle disease: GSDV (n = 269) in 5–10 McArdle patients, and the other pathogenic Patient demographics variants were mostly private. Sixteen novel pathogenic Age ranged from 8–82 years, with a median age of variants, not previously reported in the Human Gene 46 years. Fifty-three percent were males (n = 142) and Mutation Database, were identified (Table 3). 47% females (n = 127). Completeness of data entry for different items is shown in Table 1. Body mass index (BMI) BMI was analysed in people older than 18 years (n = 203). Diagnosis The median BMI in this cohort was 25.9 kg/m2 (range: The median age at diagnosis was 30 years (range: 16.6–52.8 kg/m2). Abnormal BMI was observed in 62.6% 5–79 years), with no difference between men and women. (Fig. 2). Table 2 illustrates the use of the diagnostic tests (genetic testing, muscle biopsy). In total, 90.0% of patients had a McArdle‑related signs and symptoms genetic test performed at some stage of the diagnostic Most patients identified spontaneous second wind (82%, investigation. n = 187), while 41 patients (18%) had not previously rec- Of all McArdle patients with two pathogenic variants ognised the phenomenon. Baseline serum creatine kinase identified (n = 242), the allele frequency for the c.148C>T (CK) levels varied from 99 to 32,394 IU/L (median: (p.R50X) variant was (62.4%) occurring as either 1,475 IU/L). Twelve McArdle patients (6.8%) had base- line CK below the normal upper reference level of 240 IU/L. Ten patients (5.7%) had CK levels higher than Table 1 Incomplete data related to patients with McArdle 10,000 IU/L. Previous episodes of myoglobinuria were disease (GSDV) reported by 61.7% of patients (n = 166). 71.1% of these Missing Total number of patients patients had recurrent rhabdomyolysis. No previous epi- data (n) considered for the outcome sode of myoglobinuria was reported by 39.4% of patients analysis (n) (n = 106). Current age 1 268 Muscle weakness was observed in 127 (51.4%). The Age at diagnosis 3 266 median age of those patients was 47 years. Weakness BMI 44 203a affected men (52%) and women (48%) equally. Weakness Second wind 41 228 preferentially affected upper body and trunk muscles as CK (baseline, all) 93 176 shown in Table 4. The median age of patients not affected CK (baseline/ weakness) 39 88b by muscle weakness was also 47 years. Analgesia use 91 178 There were no significant differences in CK levels in Comorbidities 28 241 patients with weakness compared with those with no a weakness (Table 5) although five of the patients with Only patients aged 18 years or older were included in the data analysis for body mass index (BMI) weakness had CK lower than 240 IU/L. Eight patients b Creatine kinase (CK) levels are shown for all patients in whom it was measured (3.2%) had ptosis (median age: 54.5 years) and in one of at baseline and the subset of patients who were affected by muscle weakness Table 2 Diagnostic investigations and age at diagnosis Diagnostic test n (%) Age at diagnosis Current age median age (age range) median age (age range) Genetic test (only) 101(37.5%) 27.5 years (8–79) 43 years (10–80) Muscle biopsy (only) 27 (10.0%) 30 years (12–58) 50 years (16–75) Muscle biopsy + Genetic test 141 (52.4%) 32 years (5–76) 46 years (8–82) Total 269 Scalco et al. Orphanet J Rare Dis (2020) 15:330 Page 4 of 8 Table 3 List of pathogenic variants assessed in 242 Table 3 (continued) patients with McArdle disease Mutation Heterozygous Homozygous Mutation Heterozygous Homozygous c.1475G>A 1 0 c.148C>T 86 108 c.1094C>A 1 0 c.613G>A 21 5 c.1093-2A>G 1 0 c.2262delA 13 4 c.1275delG 1 0 c.1190T>C 8 0 c.507G>T 0 1 c.808C>T 6 0 c.558delC 1 0 c.1A>G 1 5 c.345+2T>A 1 0 c.2392T>C 7 0 c.597-598delT 1 0 c.1466C>G 4 0 p.V25fs51Xθ 0 1 c.1282C>T 3 0 c.1477delC 1 0 c.13_14delCT 3 0 c.227delG 1 0 c.1129A>T 2 0 c. 2178+1G>A 1 0 c.1162_1169delTGG​CCG​GTinsA 2 0 c.1478T>C 0 1 c.1366G>A 2 0 c.1700A>C 0 1 c.1468+1G>A 2 0 c.1700A>G 1 0 c.1760T>C 2 0 Pathogenic variants are listed according to their frequency. Numbers in columns c.1769G>A 1 1 below the headings “heterozygous” and “homozygous” show number of persons carrying the pathogenic variant in a compound heterozygous or homozygous c.1827G>A 2 0 state. Pathogenic variants that are in italic are novel pathogenic variants not c.2056G>A 2 0 present in Human Gene Mutation Database. θ signifies frameshift pathogenic variants where the nucleotide change is unavailable c.2113_2114delGG 2 0 c.2128_2130delTTC​ 0 2 c.2143C>T 2 0 them, ptosis was the only evidence of muscle weakness. c.2385_2386delAA 2 0 Relationship between genotype and laboratory/clinical c.415C>T 1 1 findings can be viewed in Additional file 1: Table S1. c.481C>T 2 0 Forty-two patients (23.6%) used analgesic medication c.661-601G>A 1 1 to manage pain symptoms, which included: paracetamol c.1345G>A 2 0 (n = 19), nonsteroidal anti-inflammatory drugs (n = 17), c.1768+1G>A 2 0 opioids (n = 14), central analgesic (n = 5) and steroids c.2259_2261delA 1 1 (n = 1). c.1275-1276insG 2 0 c.2177+1G>A 2 0 Cardiorespiratory fitness (peak oxygen uptake ­[ VO2peak]) c.773-2A>T 1 0 A cycle ergometry exercise test was performed in 71 c.1463C>T 1 0 patients in Spain (n = 41), Italy (n = 14), United King- c.1723A>G 0 1 dom (n = 9) and Denmark (n = 7); one exercise test was c.1730A>G 1 0 excluded from data analysis as the cycle test was inter- p.R387Afs*37θ 1 0 rupted prematurely. The median V ­ O2peak was 18.5 ml/ c.1805G>A 1 0 kg/min (7–33). This value is a little less than half that c.1948C>T 1 0 expected in matched healthy people. The lowest result c.2075_2076delCCinsAAA​ 1 0 was seen in a 48-year-old woman with fixed muscle c.2083G>A 1 0 weakness. c.2441G>A 1 0 c.244-3_244-2delCA 1 0 Comorbidities c.255C>A 1 0 In this cohort, 80 people (33.2%) did not have any comor- c.347T>C 1 0 bidity (median age: 34 years). Recorded comorbidities are c.458T>G 1 0 shown in Table 6. Median age of patients with comor- c.580C>T 1 0 bidities was 50 years (12–82). Hypothyroidism affected c.715_717delGTC​ 1 0 men (n = 7) and women (n = 7) equally (age range at c.1093-1G>T 1 0 data entry: 17 – 77 years; median age: 59.5 years; mean c.1239+1 1 0 age: 52.5 years). The two thyroid gland tumors reported c.397G>A 1 0 were a benign adenoma and a malignant carcinoma. Scalco et al. Orphanet J Rare Dis (2020) 15:330 Page 5 of 8 Fig. 2 Body mass index (BMI) in 203 adult patients with McArdle disease (GSDV). Underweight: < 18.5; Normal weight: 18.5–24.9; Overweight: 25.0–29.9; Obese I: 30.0–34.9; Obese II: 35.0–39.9; Obese III: ≥ 40 kg/m2 Table 4 Muscle weakness in 127 adults with McArdle failure, 17 had a positive history for a previous episode of disease myoglobinuria. Thyroid problems (n = 20) were the most Affected muscles n frequent among the endocrine diseases, with prevalence higher than diabetes (n = 15). Upper limbs/trunk 74 Lower limbs 21 Discussion Upper and lower limbs + trunk 31 Besides a specific international Pompe disease registry, Ptosis 8 EUROMAC is the only international registry of muscle Mastication muscles 1 glycogenoses reported to date that serves as a pan-Euro- The total number of patients in the table exceeds 127 as 7 of 8 patients with pean reference to register people with rare muscle GSDs ptosis and the patient with affection of the masticatory muscles also had limb or truncal weakness. Weakness in upper and lower limbs and trunk, was defined as to improve knowledge and promote research in these weakness of one or more muscle groups in each region conditions. Besides unravelling phenotype characteristics of McArdle disease as discussed below, the EUROMAC Table 5 Serum creatine kinase (CK) levels in patients project also played a key role in education and training in according to muscle weakness several European countries. The registry has also contrib- uted to the promotion and/or implementation of interna- Median CK (IU/L) Range (IU/L) tional clinical trials [10–21], illustrating its positive role Weakness 1519.5 137–32,394 in promoting translational research. No weakness 1271 99–25,459 The most common muscle GSD represented in this European cohort was McArdle disease. Although data on age at onset of symptoms were not recorded in the registry, because of a presumed high level Ophthalmological conditions included retinal problems of recall bias, there seems to be a considerable delay in (n = 3), cataract (n = 1) and uveitis (n = 1). Retinal prob- diagnosing the GSDs, which highlights the need for bet- lems included macular degeneration, retinoschisis and ter awareness of these conditions. So, besides creating a history of three retinal detachments, and retinal dys- the EUROMAC registry, it emphasizes the importance trophy. Of the 19 patients with a history of acute kidney of the EUROMAC education and dissemination activities Scalco et al. Orphanet J Rare Dis (2020) 15:330 Page 6 of 8 Table 6 Comorbidities reported facilitate more timely diagnosis of muscle GSDs. The reg- Comorbidities N Frequency in this Median age istry confirmed the high prevalence of the two common Cohort (n = 241) (range) Years variants, c.148C>T (p.R50X) and c.613G>A (p.G205S) in (%) the European population of McArdle patients, and added Hypertension 41 17 57 (39–82) 16 novel pathogenic variants to the list of approximately Endocrine disease (Total) 38 15.7 56 (17–77) 150 known, pathogenic PYGM variants. Diabetes 15 As previously reported, the serum CK levels were high Hypothyroidism 14 in most patients with McArdle disease, however, it was Thyrotoxicosis 2 surprising to find that 6.8% of patients had CK levels within normal range. All patients with normal CK levels Thyroid tumour 2 had a confirmed genetic diagnosis and had typical symp- Hyperthyroidism 2 toms of McArdle disease, such as exercise-induced pain Other endocrine problems 3 and contractures and exercise intolerance, which led to Musculoskeletal/rheumatic 31 12.9 52 (15–82) disease diagnostic testing for the disease. Four of the patients Coronary artery disease 20 8.3 62 (42–80) with normal CK levels had a history of myoglobinuria. Other cardiovascular disease 10 4.1 54.5 (35–80) Normal CK levels were also seen in more severely Hyperuricemia/gout 28 11.6 60.5 (24–80) affected people, including those with fixed muscle weak- Gastroenterological dis‑ 27 11.2 52 (12–77) ness. An important message therefore is that a normal ease (Total) CK and a negative history for myoglobinuria do not Gall bladder problems 6 exclude a diagnosis of McArdle disease. Hiatus hernia and/or acid 4 There was a higher frequency of fixed muscle weakness reflux reported in this cohort compared with previous studies Crohn’s disease 3 of patients of the same age [23, 24, 26], suggesting that Irritable bowel syndrome 3 this condition may have been under-recognized in the Coeliac disease 3 past. A major new finding from our registry data was the Diverticulitis or polyposis 2 presence of ptosis in a small proportion of patients with Constipation 1 McArdle disease, suggesting that this can also be a fea- Gastritis 1 ture of this glycogenosis, as it has also been noticed in Liver ­diseasea 4a patients with GSDII (Pompe disease) [27, 28]. a Pancreatitis 2a We also found that BMI was higher than normal in Neurological disease 24 10 51.5 (13–81) almost two thirds of patients, likely reflecting a sedentary Respiratory disease 23 9.5 51 (12–75) lifestyle related to the poor exercise tolerance and mus- Acute renal failure 19 7.9 53 (33–76) cle pain on exertion. This is relevant for these diseases Chronic renal failure 3 1.2 44 (17–49) as overweight and general low physical activity level Dyslipidaemia 21 8.7 57 (24–82) promotes low insulin sensitivity, diabetes and metabolic Mental disorder (Total) 16 6.6 49 (13–75) syndrome, factors that may exacerbate the condition. Depression 9 Coronary artery disease was the most common heart Anxiety 4 disorder. Surprisingly, thyroid disease was the most com- Bipolar disorder 1 mon endocrine disorder, with a higher frequency than Schizophrenia 1 diabetes. The prevalence of hypothyroidism is 1–2% in Post-traumatic stress 1 iodine-sufficient parts of the world [29], which is lower disorder than the prevalence reported in the present study (5.8%). Cancer 11 4.6 55 (33–82) This is the first time an increased frequency of thyroid Anaemia/hyperbilirubinemia 9 3.7 39 (26–82) problems was reported in people affected by McArdle Ophthalmological disease 5 2.1 67 (60–73) disease, but the reason for this warrants further study. Others 54 22.4 53 (19–80) The authors recommend performing regular TSH sur- a Two patients had two gastroenterological diseases: Thus, the sum in the table veillance for patients at their follow-up visits. is higher than the total number of patients affected by a gastroenterological disease Three patients had chronic renal failure, indicating that recurrent rhabdomyolysis, which is common in this population, rarely results in irreversible kidney dam- [22–25]. The increased use of genetic diagnostic testing age. Three patients had retinal problems. Even though a reflects the shift towards a molecular genetic approach recently published case series has identified four more across all participating countries, which likely will McArdle patients with retinal disease [30], it is still Scalco et al. Orphanet J Rare Dis (2020) 15:330 Page 7 of 8 uncertain whether this is part of the disease. The possi- and interpretation and drafting the manuscript. ALA: coordination of the EUROMAC proposal and creation of the consortium. RM and TP: coordina‑ bility of associated retinal disease should be explored fur- tion of the EUROMAC project and registering activity. All authors read and ther, and therefore a retinal exam should be performed at approved the final manuscript. least once in patients. Funding Limitations of this study include the collection of ret- EUROMAC was funded by the European Commission’s Consumers, Health, rospective data and the presence of missing data. Further Agriculture and Food Executive Agency (CHAFEA, Grant 2012-12-14 to efforts to maintain a prospective registry for rare diseases the EUROMAC consortium), and by the Spanish Instituto de Salud Carlos III, co-funded by the European Regional Development Funds, ERDF (Grants may help gaining further understanding on the natural PI16/01492, PI19/01313 and CIBERER-ACCI 2016-03, to TP). history of rare conditions such as McArdle disease. Availability of data and materials Nearly all data relevant to the study is included in this article. Other data are Conclusions available upon reasonable request, if ethic committees involved grant permis‑ The EUROMAC project and international registry have sion to do so. significantly raised awareness of McArdle disease, and Ethics approval and consent to participate should inspire opinion leaders in other fields to develop The project was approved by the Institutional Review Board of the Coordinat‑ similar patient registries. ing Center (Vall d’Hebron Research Institute, Barcelona), and by review boards of each institution recruiting participants. The analysis of the registry data has given insight into new phenotypic features of McArdle disease and the Consent for publication variety of co-comorbidities affecting people with McAr- Not applicable. dle disease, which should lead to strategies reducing Competing interests and managing these in the future, including controlling The authors declare that they have no competing interests. weight, and preventive screening for thyroid and coro- Author details nary artery diseases. The data of the registry suggest that 1 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, physical examination should focus more on occurrence National Hospital, London, UK. 2 Faculty of Sport Sciences, Universidad of ptosis and fixed muscle weakness, which may be over- Europea de Madrid, Madrid, Spain. 3 Instituto de Investigación Hospital, 12 de Octubre (imas12), Madrid, Spain. 4 Universidad Pablo de Olavide, Seville, looked, and stresses the need not to discard a diagnosis Spain. 5 Dept. of Conegliano‑Pieve Di Soligo, IRCCS Medea Scientific Insitute, of McArdle disease even though CK is normal and epi- Bosisio Parini, Italy. 6 Neurology and Neuromuscular Diseases Unit, Depart‑ sodes of myoglobinuria are absent. ment of Clinical and Experimental Medicine, University of Messina, Messina, Italy. 7 Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Nether‑ Supplementary information lands. 8 Nord/Est/Ile de France Neuromuscular Reference Center, Neurology Supplementary information accompanies this paper at https​://doi. Department, Raymond‑Poincaré Teaching Hospital, Garches. AP‑HP. INSERM org/10.1186/s1302​3-020-01562​-x. U1179, END‑ICAP, Paris Saclay University, Paris, France. 9 Pathology Deparment, Alvaro Cunqueiro Hospital, Vigo, Spain. 10 Rare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS- Additional file 1. Genetic variants according to clinical features. UVIGO, Vigo, Spain. 11 Neurology and Neuromuscular Diseases Unit, Depart‑ ment of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 12 Department of Neurology, Heimer Institute for Muscle Research, University Abbreviations Hospital Bochum, Bochum, Germany. 13 Peripheral Nervous System and Mus‑ AGSD-UK: Association for Glycogen Storage Disease (UK); CK: Creatine kinase; cle Department, CHU Nice, Université Côte D’Azur, Institute for Research On GSD: Glycogen storage disease; GSD-V: Glycogen storage disease type V; Cancer and Aging of Nice (IRCAN), INSERM U1081, CNRS UMR 7284, Faculty VO2peak: Peak oxygen uptake; NSAID: Non-steroidal anti-inflammatory drugs; of Medicine, Université Côte D’Azur (UCA), Nice, France. 14 Copenhagen WP: Work package. Neuromuscular Center, Section 6921, Rigshospitalet, University of Copenha‑ gen, 2100 Copenhagen, Denmark. 15 Istanbul Faculty of Medicine, Istanbul Acknowledgements University, Istanbul, Turkey. 16 Department of Neurology, Medical University EUROMAC was supported by several patients’ associations and large networks of Warsaw, Warsaw, Poland. 17 Association for Glycogen Storage Disease (UK), of patient registries, such as the Association for Glycogen Storage Disease Bristol, UK. 18 Biomedical Network Research Centre on Rare Diseases (CIBERER), (https​://agsd.org.uk/) and the EPIRARE Group on Rare Disease Registries (https​ Instituto de Salud Carlos III, and Research Group on Neuromuscular and Mito‑ ://www.euror​dis.org/conte​nt/epira​re). The European Neuromuscular Centre chondrial Diseases, Vall d’Hebron Research Institute, Universitat Autònoma de (https​://www.enmc.org/) also supported the project by contributing to the Barcelona, Barcelona, Catalonia, Spain. organization and funding of a dedicated workshop. EUROMAC Consortium: Antoni L. Andreu, Ramon Martí, Tomàs Pinós, Received: 24 April 2020 Accepted: 25 September 2020 Noemi Baruch, Francisco J. Ortega, Miguel A. Martín, Carmen Navarro, Beatriz San Millán, Irene Vieitez, Andrea Martinuzzi, Monica Castelli, Federica Zucchi, Claudio Bruno, Antonio Toscano, Olimpia Musumeci, Pascal Laforêt, Sabrina Sacconi, Ros Quinlivan, Renata Scalco, Andrew Wakelin, Georgios Hadjgeor‑ giou, Elias Zintzaras, John Vissing, Matthias Vorgerd, Enrico Zülow, Ronald References Haller, Piraye Oflazer, Hacer Durmus, Jean Pouget, Alejandro Lucia, Alfredo 1. Augustine EF, Adams HR, Mink JW. Clinical trials in rare disease: challenges Santalla. and opportunities. 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Muscle glycogen synthesis and breakdown are both impaired in glycogenin-1 deficiency. Neurology. 2017;89(24):2491–4. Publisher’s Note 17. Voermans NC, Preisler N, Madsen KL, Janssen MC, Kusters B, Abu Bakar Springer Nature remains neutral with regard to jurisdictional claims in pub‑ N, Conte F, Lamberti VM, Nusman F, van Engelen BG, van Scherpen‑ lished maps and institutional affiliations. zeel M, Vissing J, Lefeber DJ. PGM1 deficiency: substrate use during Ready to submit your research ? Choose BMC and benefit from: • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations • maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions