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Section Page1 Introduction 32 General background 32.1 Overview 32.2 History 42.3 Nomenclature 42.4 Clinical overview 42.5 Clinical variability 52.6 Epidemiology 53 Methods/process 53.1 Consensus development panel 53.2 Target audience 54 Diagnosis 54.1 Dierential diagnosis 54.2 Misdiagnosis 64.3 Genetics 6 Fig. 1. Dierential diagnosis 74.4. Muscle biopsy 84.5 ‘Second-wind’ as a diagnostic aid 84.6 Other 85 Overview of management 85.1 Centre of expertise 85.2 Benets of regular assessment 85.3 Laboratory testing 95.4 Information & guidance for day-to-day management 95.4.1 Use of second-wind in GSD V 95.4.2 Physical activity, aerobic conditioning 95.4.3 Physical activity, strength training 95.5 Dietary management 105.5.1 GSD V 105.5.2 GSD VII 10Appendix Page1 McArdle Energy Reservoir 202 Clinical Variability 213 Physical Training Guidelines 22Section Page5.6 Cramps and contractures 105.7 Pain management 106 Medical emergencies 116.1 Rhabdomyolysis 116.2 Acute renal failure 116.3 Compartment Syndrome 116.4 Haemolytic anaemia in GSD VII 126.5 Rehabilitation protocol 127 General medical care 127.1 Considerations for general practitioners 127.2 Concomitant conditions 137.3 Potential drug–disease interactions 138 Surgery 139 Obstetric care 1310 Publications and resources 1411 Emerging issues and knowledge gaps 1411.1 Impact on carriers 1411.2 ird wind in GSD V? 1411.3 LCKD in GSD V 1411.4 Cognitive impairment 14IamGSD Study Group 14Acknowledgments 15Disclosures 15Funding 15Supplementary material 15References 15International Study Group full list 18Clinical practice guidelines for glycogen storage disease V & VII (McArdle disease and Tarui disease) from an international study groupCONTENTS Supplementary Material 19Clinical Practice GuidelinesAppendix Page4 Concomitant Conditions 285 Publications and Resources 32References for these appendices 34

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Neuromuscular Disorders 31 (2021) Page 3Available online at www.sciencedirect.com Neuromuscular Disorders 31 (2021) 1296–1310 www.elsevier.com/locate/nmd Clinical practice guidelines for glycogen storage disease V & VII (McArdle disease and Tarui disease) from an international study group Alejandro Lucia a , b , Andrea Martinuzzi c , Gisela Nogales-Gadea d , Ros Quinlivan e , Stacey Reason f , ∗, on behalf of the International Association for Muscle Glycogen Storage Disease study group 1 a Faculty of Sports Sciences, Universidad Europea de Madrid, Spain b Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES) and Research Institute of the Hospital 12 de Octubre (‘imas12’, PaHerg group), Madrid, Spain c Conegliano Research Centre, IRCCS Eugenio Medea, Italy d Institut d’Investigació Germans Trias i Pujol, Camí de les Escoles, Barcelona, Spain e MRC Centre for Neuromuscular Disease, National Hospital for Neurology and Neurosurgery, London, UK f International Association for Muscle Glycogen Storage Disease, California, USA Received 12 October 2021 1. Introduction By an initiative of the International Association of Muscle Glycogen Storage Disease (IamGSD), an international workshop was organised in the form of several digital meetings to provide a document as a resource for clinicians regarding current best practice related to diagnosis and management of Glycogen Storage Diseases (GSDs) V (McArdle) and VII (Tarui). 2. General background 2.1. Overview Glycogen is the stored form of glucose, which is primarily derived from ingested carbohydrates. In order to break down glycogen for energy, the coordinated action of a number of enzymes is required; GSDs result from a defect in one of these enzymes. There are three isoforms of phosphorylase, an enzyme encoded by any of three genes depending on cell type, muscle ( PYGM gene), liver ( PYGL gene), and brain ( PYGB gene). GSD V is the most common muscle GSD, and results from a deﬁciency in the muscle isoform of glycogen phosphorylase (myophosphorylase) [1] . A deﬁciency of this enzyme disables ∗Corresponding author. E-mail address: stacey.reason@iamgsd.org (S. Reason). 1 Listed at the end of this report. the breakdown of muscle glycogen into glucose-1-phosphate, resulting in a block in glycogenolysis. However, glycolysis is only partially blocked in GSD V, as muscle ﬁbres can take up serum glucose and convert it to glucose-6-phosphate downstream of the metabolic block [2] . The primary intramuscular and extramuscular substrates of skeletal muscle metabolism include: (a) muscle glycogen; (b) blood glucose derived from liver glycogenolysis and from gluconeogenesis, as well as from the gut when carbohydrate is ingested; and (c) fatty acids derived from both intramuscular triacylglycerides and triacylglyceride in adipose tissue [3] . Because skeletal muscle relies predominantly on anaerobic energy for the ﬁrst few minutes as it transitions from rest to activity, and throughout more intense activities, individuals with GSD V experience muscle fatigue and pain, tachypnea, and tachycardia very soon after initiating physical activity and during all intense activities. If these warning signs are not heeded, a muscle contracture may occur very rapidly which could lead to rhabdomyolysis. Unique to GSD V is a phenomenon called ‘second-wind’, which typically occurs about 6 to 10 min into physical activity. It was originally identiﬁed by Pearson et al (1961), and denotes a marked improvement in the capacity for physical activity such that activity that previously caused fatigue becomes more easily tolerated [4] . ‘Second-wind’ is marked by a dramatic fall in heart rate, commonly by 20 to as much as 50 beats per minute, by an improved ability of working muscle to extract oxygen and substrates from https://doi.org/10.1016/j.nmd.2021.10.006 0960-8966/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

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Clinical Practice Guidelines for GSD V and VIIPage 4A. Lucia, A. Martinuzzi, G. Nogales-Gadea et al. Neuromuscular Disorders 31 (2021) 1296–1310 arterial blood, by a marked fall in perceived exertion, and often by a decrease in ventilation and breathing effort. The basis of this improved physical activity tolerance has long been recognised to relate to a change in muscle metabolism. At approximately 6 to 10 min of sustained physical activity a nadir of oxidative capacity occurs, which is then followed by improved oxidative capacity attributable to increased delivery, uptake, and metabolism of alternative fuels (such as free fatty acids (FFA), glucose, and amino acids) that increase oxidative capacity, on average, by 25%. There are three isoforms of Phosphofructokinase, a tetrameric enzyme encoded by any of three genes depending on cell type, muscle ( PFKM gene), liver ( PFKL gene), and platelet ( PFKP gene). In GSD VII there is a complete block in glycolysis due to a deﬁciency of the enzyme muscle phosphofructokinase, whereas normal isoforms are present in the liver and platelets [5] . Muscle phosphofructokinase is a glycolytic enzyme that catalyses the conversion of fructose 6-phosphate to fructose 1,6-bisphosphate. Accordingly, use of both muscle glycogen and blood glucose is blocked, resulting in a metabolic shift to a non-glycolytic anaerobic pathway, which has by-products of uric acid and ammonia. A GSD V style of ‘second-wind’ does not occur in GSD VII, thereby increasing the reliance on fat metabolism. Ingestion of glucose prior to exercise in individuals with GSD VII worsens exercise capability, leading to an ‘out-of-wind’ phenomenon [6] . Isolated and unconﬁrmed cases of a severe infantile form of GSD VII have been reported. 2.2. History In the 1920s, several hepatic forms of glycogenosis were described and in 1932 the ﬁrst muscle glycogenosis, Pompe disease (type II) [7] , was described. GSD V was described in 1951 by Dr. Brian McArdle [8] . He elegantly demonstrated that lactate from an efﬂuent vein draining from an exercising muscle did not increase during exercise. At the same time, he showed that glucose could be mobilised from the live r after norepinephrine injection, which indicated intact liver glycogenolysis. He therefore correctly deduced that the patient had a disorder of muscle glycogen breakdown. In 1959, it was shown that the affected enzymatic step was myophosphorylase [ 9 , 10 ]. In 1984, the gene encoding myophosphorylase ( PYGM ) was discovered [11] . GSD VII was ﬁrst described by Dr. Seiichiro Tarui [12] in Japanese patients, and then in an Ashkenazi Jew [13] . Although more than 50 years have passed since its discovery, GSD VII remains a ve ry rare muscle GSD. 2.3. Nomenclature GSD V is also referred to as McArdle disease, McArdle’s syndrome, Muscle Phosphorylase Deﬁciency, Myophosphorylase Deﬁciency, McArdle Myopathy, Muscle Glycogen Phosphorylase Deﬁciency, GSD Type 5 and GSD5. GSD VII is also referred to as Tarui disease, Muscle Phosphofructokinase Deﬁciency, GSD Type 7, and GSD7. McArdle disease and Tarui disease will hereafter be referred to as GSD V and GSD VII, respectively. 2.4. Clinical overview The main feature of both GSD V and GSD VII is ‘physical activity intolerance’. In almost all papers to date, this has been referred to as ‘exercise intolerance’. However, exercise, a subcategory of physical activity, is planned and controlled, thereby making it easier to manage. By contrast, activities of daily living (ADL) are often spontaneous, and symptoms can occur within seconds to minutes after initiation. Accordingly, we use the term ‘physical activity intolerance’ throughout. Despite a long history of activity limitations, many individuals only receive a diagnosis as the result of an incidental ﬁnding of elevat ed serum creatine kinase (CK). The inability to sustain muscle effort can objectively be measured during incremental exercise tests, in which the maximal work performed is usually < 50% of what might be expected for age- and gender-matched controls. Premature physical activity intolerance is mainly associated with muscle fatigue and activity-induced muscle pain, and 30% of patients with GSD V report chronic pain [14] . Pain intensity is reported as moderate (mean numerical reporting scale (NRS) 5.43/10) and mostly cramp-like. The impact of physical activity intolerance and pain on ADLs and instrumental ADL (iADL) has been investigated and it is reﬂected in the widely used ordinal (0-3) grading of severity of disease [15] . In the combined Spanish and Italian GSD V cohort (380 patients), there was no reported impact on ADL (grade 0) in 7% of the patients, mild to moderate impact in 70%, and substantially severe impact in 23%. An assessment of disability in 14 adults with GSD V using the World Health Organisation – Disability Assessment Schedule (WHO-DAS) 2.0, showed an equal distribution of mild difﬁculties in four activity domains: mobility, social life, household tasks, and work (Martinuzzi, A. unpublished results). The evaluation of perceived quality of life (QoL) with the Short Form 36 (SF36) in the same group yielded the worst results in the domains of health-related role limitation (40), general health, pain, energy/fatigue and emotional wellbeing (50). When exploring the types of activity that trigger pain or result in a limitation in the intensity and/or duration of the activity, spontaneous iADL such as lifting heavy objects, climbing stairs or running are among the most frequently reported. Most patients with GSD V learn to circumvent the limitations by implementing adaptive strategies, either by taking advantage of the ‘second-wind’ phenomenon or by avoiding overload of single muscle groups with sustained contraction. To help patients understand when muscle damage may occur, please refer to Supplementary Material - Appendix 1 . The impact of the disease on activities, and the evaluation of the modulating effect of the environmental factors, should be evaluated in patients with GSD V and GSD VII with 1297

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Neuromuscular Disorders 31 (2021) Page 5A. Lucia, A. Martinuzzi, G. Nogales-Gadea et al. Neuromuscular Disorders 31 (2021) 1296–1310 appropriate tools: for example, the WHO-DAS 2.0 [16] . The same systematic approach should be followed for the evaluation of the QoL. GSD VII is also characterised by physical activity intolerance, muscle cramps and, following intense activity, nausea and vomiting. Jaundice, elevated CK, hyperuricaemia, reticulocytosis, and increased serum bilirubin may also be observed. The late onset form presents with myalgia later in life and may lead to severe disability. The unconﬁrmed infantile form may present as ‘ﬂoppy babies’ with a lifespan of one year. Lastly, the haemolytic form presents with non- spherocytic haemolytic anaemia and no muscle involvement [17] . Job/task speciﬁc adaptation is sometimes needed for patients with GSD V or VII, and consideration of these strategies should be part of the treatment protocols. 2.5. Clinical variability There is heterogeneity in the clinical manifestation of GSD V, which complicates diagnosis and understanding of this condition. In the last update of the Spanish registry of patients [18] , 8% of patients reported themselves as asymptomatic during normal daily life. By contrast, 21% of patients reported episodes of recurrent myoglobinuria, ﬁxed muscle weakness mostly affecting the upper body, and sometimes associated muscle wasting. These individuals were severely limited in most ADLs. The PYGM gene, which encodes myophosphorylase, has no genotype-phenotype correlation, as reported in various cohorts [18–21] . In one series, most documented PYGM mutations have functional consequences, and patients’ muscles are devoid of myophosphorylase activity, independent of clinical manifestations [18] . However, splice mutations in PYGM have been reported to preserve some myophosphorylase activity and attenuate the phenotype in single cases of GSD V, but this is extremely rare, and thus the overall conclusion of no phenotype-genotype correlation is likely to hold true [22] . Age negatively affects functional capacity in everybody, whereas regular physical activity has the opposite effect. Individuals with GSD V or GSD VII are advised to engage in regular exercise in order to improve cardiorespiratory function (CRF) and ultimately to improve the clinical course of the disease. Factors that may inﬂuence functional capacity in GSD V and GSD VII are highlighted in Supplementary Material - Appendix 2 . 2.6. Epidemiology The variance between the prevalence based on genetic data and the prevalence based on diagnosed cases may be due to the average delay in correct diagnosis. In the Dallas/Fort Worth area of the USA, the prevalence of GSD V based on genetic data is estimated to be 1/100,000 [23] . A study of diagnosed cases in Spain indicates a prevalence of ∼1/139,543, [18] . However, a study of next-generation sequencing (NGS) data predicts a prevalence of between 1/7650 (based on six common mutations) and 1/42,355 (based on the two most common mutations) [24] . GSD VII is considered to be very rare, with only around 100 to 200 reported cases worldwide. Symptoms may be attributed to poor ﬁtness, so a lack of recognition and diagnosis may mean the true prevalence is much higher. Ashkenazi Jews share two common mutations in the PFKM gene, which may account for the higher prevalence amongst this population. Both GSD V and GSD VII are inherited in an autosomal recessive pattern. In regard to gender, in GSD V cohorts the following ratios of males to females have been observed: Spain 55:45 [18] ; Italy 65:35 [25] ; UK 50:50 [20] . Equality is expected in an autosomal recessive condition. Where there is a predominance of affected males, this may be due to gender- related reporting bias, as males are more likely to undertake strenuous recreational and occupational activities. 3. Methods/process 3.1. Consensus development panel An international group of experts was assembled to review the current evidence base in GSD V and GSD VII for (1) clinical variability; (2) clinical and laboratory diagnosis; and (3) management (exercise, nutrition, medical emergencies, general medical care, surgery, and obstetric care) in order to develop management guidelines for these areas. Group members were assigned sections speciﬁc to their areas of expertise. The terms cited in Section 2.3 were included in the search of PubMed. Where the current evidence base was insufﬁcient, expert opinion was sought, and consensus was applied. The participants provided conﬂict of interest statements and these are included in the Disclosure section. An external review group reviewed a penultimate draft of these CPGs. The study group reviewed their suggestions and made amendments as appropriate. All members of the Consensus Development Panel reviewed and approved the ﬁnal CPG. 3.2. Target audience The overa ll impact of GSD V and GSD VII can be nuanced, resulting in a cascading effect on multiple systems, including the skeletal, muscular, nervous, cardiovascular, urinary, respiratory, and ocular systems. For this reason, these guidelines were developed to support clinicians in multiple disciplines across the continuum of care and the lifespan of patients. 4. Diagnosis 4.1. Differential diagnosis The clinical manifestations of GSD V and GSD VII typically begin in childhood [ 26 , 27 ]. The clinical signs and symptoms of GSD V and GSD VII are common to all 1298

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Clinical Practice Guidelines for GSD V and VIIPage 6A. Lucia, A. Martinuzzi, G. Nogales-Gadea et al. Neuromuscular Disorders 31 (2021) 1296–1310 glycolytic disorders. Basal CK is typically raised in GSD V, but may be normal in GSD VII. Other non-glycolytic myopathies can also present with physical activity-induced muscle pain, rhabdomyolysis, myoglobinuria, and raised basal CK ( Fig. 1 ). The phenomenon of ‘second-wind’ might not be so easy to detect in young children [28] . It may also prove difﬁcult at this age to perform a non-ischaemic forearm exercise test, and no study has been conducted to determine whether this provides conclusive data. Haematological ﬁndings, namely haemolytic anaemia, may point to a diagnosis of GSD VII. In brief, the differential diagnosis for these diseases is highly complex, and diagnosis of these patients is challenging for clinical care professionals. Although these are rare disorders, the ﬁrst presentation is usually before the age of 10 and paediatricians should consider these pathologies, and nowadays the ﬁrst approach is often genetic testing. In adults, a patient self-report of ‘second-wind’ or a ﬂat lactate response with a rise in ammonia levels after a non-ischaemic forearm exercise test may be helpful to guide the differential diagnosis. 4.2. Misdiagnosis Ninety percent of people with GSD V received a misdiagnosis before a corrected diagnosis (GSD VII unknown), resulting in a median diagnostic delay of 29 years, which can seriously affect QoL [29] . The onset of symptoms typically occurs in childhood with ﬁrst presentation to a general practitioner (GP) before the age of 10 years; however, the median age of correct diagnosis is age 33. Of the most commonly reported misdiagnoses, children are often dismissed by GPs as ‘lazy or unﬁt’ (51% of patients), or having ‘growing pains’ (44%). Of those who are misdiagnosed, 62% report being misdiagnosed more than once, with 47% receiving incorrect management [29] , thereby increasing the risk of muscle damage and episodes of rhabdomyolysis, which can lead to potential life- threatening complications such as acute renal failure (ARF) and acute compartment syndrome (ACS). In addition to the most common misdiagnoses, some patients receive a more generalised diagnosis of myositis [30] . A blood test to evaluate basal CK (particularly in GSD V) is a useful screening test as it is almost certain to be signiﬁcantly raised indicating the need for further investigation. Misdiagnoses are evenly split between males and females, with the exception of ‘psychological conditions’, with which females are misdiagnosed six times as frequently as males [29] . The misdiagnosis of neuromuscular diseases is likely to decrease with the increasing use of genetic testing. 4.3. Genetics From records documenting the study of the genetics of GSD V, 179 pathogenic variants have been described, the combination of which affect all the exons of the PYGM gene. Missense pathogenic variants are the most common, and the p.Arg50Ter variant is the most commonly detected variant in European and US Caucasian populations ( ∼60% of the mutated alleles). A recent publication explains the lack of genotype-phenotype correlation in GSD V. Most of the patients in the study did not have myophosphorylase activity, independent of the type of mutation (missense, nonsense, deletion, insertion, splicing, etc.) [31] . This indicates that myophosphorylase is not produced in the presence of PYGM mutations, except for very rare cases in which missense mutations lead to preserved myophosphorylase activity and ameliorated phenotypes [22] . There is no clear relationship between clinical severity, PYGM genotype and biochemical analysis of muscle samples. The clinical phenotype may be modiﬁed by the genotype of the angiotensin-converting-enzyme (ACE) gene [ 15 , 32 ]. The diagnosis of GSD V can be made after taking a careful clinical history, and with the observation of raised serum CK, and is conﬁrmed using minimally invasive methods based on the molecular analysis of the PYGM gene on deoxyribonucleic acid (DNA) obtained from peripheral blood samples. Molecular genetic testing is clinically available through Sanger sequencing of PYGM, NGS panels which include PYGM (such as for all GSDs or for rhabdomyolysis), or whole exome sequencing (WES). Identiﬁcation of two pathogenic variants in suspected patients is required for conﬁrmation of diagnosis. Based on the knowledge of common mutations in Caucasian and Japanese patients or individual families, DNA- based targeted mutation testing can be offered. If only one (or no) pathogenic variant is detected, Sanger sequencing of PYGM , followed by deletion/duplication analysis may be indicated. In cases in which variants of unknown signiﬁcance (VUS) are detected, a functional exercise test such as a cycle test may be helpful, as may a non-ischaemic forearm test and muscle biopsy for muscle phosphorylase enzyme activity. In the case of GSD VII, 27 pathogenic variants are described in the Human Gene Mutation Database. GSD VII has marked phenotypic and genotypic heterogeneity, and the majority of mutations result in markedly reduced activity of the enzyme [33–36] . Reported variants include deletions, duplications, intronic deletions, insertions, and single nucleotide changes. GSD VII is especially prevalent in the Ashkenazi Jewish population, with the most prevalent pathogenic variant being a splicing defect in the 5  donor site, which results in an in-frame deletion of exon 5 sequence. Japanese, Ashkenazi, and non-Ashkenazi European ethnic groups account for virtually all known pathogenic variants in the PFKM gene [33–36] . Genetic testing can be performed using single-gene Sanger sequencing or using myopathy or rhabdomyolysis gene panels or WES with peripheral blood samples [ 33 , 36 ]. Where disease-causing family mutations are known to exist in a proband, targeted mutation analysis can be performed. Prenatal diagnosis is not indicated for these disorders [ 18 , 37–39 ]. 1299

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Clinical Practice Guidelines for GSD V and VIIPage 8A. Lucia, A. Martinuzzi, G. Nogales-Gadea et al. Neuromuscular Disorders 31 (2021) 1296–1310 4.4. Muscle biopsy When VUS are observed, and exercise tests are inconclusive, a biochemical or histochemical demonstration of the enzymatic defect in the muscle biopsy tissue may be used. [ 18 , 40 , 41 ]. In GSD V, muscle biopsy specimens usually show markedly increased levels of subsarcolemmal glycogen accumulation (3 to 5 times the normal range) with normal glycogen structure [39] . The diagnosis of GSD V is conﬁrmed by enzymatic evaluation of skeletal muscle biopsy, which shows undetectable or very low levels of myophosphorylase activity [ 37 , 38 ]. Myosin-heavy-chain staining has not shown any special pattern of muscle ﬁbre type distribution in GSD V biopsies [42] . Muscle phosphorylase activity can also be suppressed due to phosphorylase kinase deﬁciency (GSD IXd) [43] . When VUS are observed, and exercise tests are inconclusive, the diagnosis of GSD VII may also be established through biochemical or histochemical demonstration of the muscle phosphofructokinase deﬁciency in muscle biopsy tissue. The muscle biopsy is characterised by glycogen accumulation by periodic acid-Schiff staining [44] or with ultra-structure analysis. Muscle glycogen content is not markedly elevated in GSD VII, although it can be mildly elevated or in the upper normal limits, with normal distribution. Muscle phosphofructokinase activity can be signiﬁcantly reduced ( < 10% of normal) or mildly reduced, indicating partial enzyme deﬁciency, in milder cases [45–47] . 4.5. ‘Second-wind’ as a diagnostic aid The utility of the ‘second-wind’ as a diagnostic indicator has been explored using both cycle ergometry and walking tests [ 48 , 49 ]. The 12 min walk test can be easily performed in the clinic setting by measuring heart rate and perceived muscle pain at each minute. It is important to remember that the ‘second-wind’ phenomenon might not be easily detectable in ver y young patients with GSD V [28] , and some individuals may require assistance to recognise ‘second-wind’. In recent years these tests have been used not only as a diagnostic aid, but also as outcome measures to detect the effects of various interventions in clinical trials [50–53] and in long term management of patients. Although the same pattern of the ‘second-wind’ phenomenon has not been observed in GSD VII patients [54] , physical activity stimulates the release of free fatty acids, thereby enabling patients with GSD VII to engage in submaximal physical activity following a period of warm-up. 4.6. Other The forearm exercise test has been used in patients with muscle GSD. Studies in GSD V have shown that a non- ischaemic version of the test is the better option, as ischaemia triggers cramps and pain in many patients, with the risk of rhabdomyolysis [55] . Even in the absence of cuff-induced ischaemia in forearm muscles, patients with GSD V show a ﬂat lactate response. Therefore, if needed, a non-ischaemic test is recommended for diagnosis of GSD V, and patients should be advised to stop the test if they experience muscle pain. Although fewer studies have been published on the forearm exercise test for the diagnosis of GSD VII, similar ﬂat lactate responses have been observed [ 56 , 57 ], and therefore the aforementioned recommendations apply. This test only indicates a block in the glycogen degradation pathway, and it is not speciﬁc for any individual muscle GSD. Electrophysiology shows myopathic features, but it is rarely required to assist with the diagnosis of people with GSD V and GSD VII. 5. Overview of management 5.1. Centre of expertise As with all rare disorders, diagnosis is frequently delayed [20] . Diagnosis and management should be undertaken by an experienced clinical team in a Centre of Excellence (CoE) that has a reasonably sized cohort of patients with GSD V or GSD VII. The goal of management should be to reduce episodes of muscle breakdown, which may result in hospital admissions for rhabdomyolysis, ARF and ACS, which are serious and potentially life threatening. In addition, patients presenting for the ﬁrst time later in life are likely to have adopted unhealthy lifestyles and have become deconditioned. As a result, they may struggle to get into ‘second-wind’, may suffer recurring pain and fatigue and may have a poor QoL. In addition, there are likely to be multiple secondary physical and psychological consequences of diagnostic delay. An expert multi-disciplinary team consisting of a physician, physiotherapist, and/or exercise physiologist, psychologist, clinical nurse specialist and dietitian is recommended to help patients overcome these difﬁculties and improve their physical activity tolerance. 5.2. Beneﬁts of regular assessment Annual assessment is recommended for most patients. Assessment may include a functional exercise test to determine physical ﬁtness/functional capacity and the ability of people with GSD V to be able to use the ‘second-wind’. This could be either a 12 min walk test [49] or a cycle test [58] . Given the higher prevalence in GSD V compared to the general population of gout (8.5: 5%), diabetes (6.7: 4.8%), myocardial infarction (11: 4%) [Quinlivan,R; unpublished data], a blood draw to test basal CK, urate, HbA1c and lipid proﬁle is recommended on an annual basis. Clinical assessment should include examination for evidence of muscle wasting and muscle weakness, as well as an assessment of gout and other medical issues. An assessment should be made of the impact of the condition on the individual with regard to their ADL, and a QoL assessment 1301

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Neuromuscular Disorders 31 (2021) Page 9A. Lucia, A. Martinuzzi, G. Nogales-Gadea et al. Neuromuscular Disorders 31 (2021) 1296–1310 should be made at each visit. A dietetic assessment should be undertaken to support avoidance of excess weight and to discuss dietary options. Patients who are deconditioned or have difﬁculty with the ‘second-wind’ should be offered additional appointments with the physical therapy team to help them practice achieving ‘second-wind’, to encourage regular physical activity and to demonstrate methods of core strengthening that are suitable for this cohort. 5.3. Laboratory testing Median basal CK elevation in a cohort of 256 individuals with GSD V was 2643 iu/L, with normal values ( < 200 IU/L) reported in only 18 individuals (7%) [53] . With episodes of rhabdomyolysis, CK levels can be much higher, even in excess of 100,000 IU/L. It is important to establish a baseline CK level by testing in the absence of injury and/or prior to initiating new medications (i.e. statins). This will help patients to better manage their condition and avoid serious episodes. It is advisable to set up a mechanism for the patient to access urgent CK testing following an injury, to help inform whether emergency management is required. CK level tends to peak 24 h after injury, and falls by approximately 30–50% per 24 h thereafter. When CK levels are above the thousands, liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are almost always elevated. This is not a sign of liver disease, but of the physiological dispersion of sarcoplasmic muscle transaminases caused by ﬁbre damage. If ALT and AST are grossly elevated disproportionate to the hyperCKemia, or if alkaline phosphatase (ALP) or bilirubin levels are signiﬁcantly raised, further investigation may be indicated. If urine test strips show blood (haemoglobin) or protein this may be myoglobin. Urate levels are often raised in GSD V due to excessive increases in blood ammonia, inosine, and hypoxanthine due to accelerated degradation of muscle purine nucleotides which serve as substrates for the synthesis of uric acid. This may lead to development of hyperuricaemia and gout. In addition, raised urate levels can lead to the development of renal stones. Routine evaluation of HbA1c and a lipid proﬁle are warranted due to the increased prevalence of diabetes and coronary artery disease for this cohort [Quinlivan, R; unpublished data]. In the case of GSD VII, episodes of rhabdomyolysis may be less frequent. In addition to muscle disease, there is erythrocyte involvement that may cause haemolysis, hyperbilirubinaemia and increased reticulocyte counts [59] . The absence of muscle phosphofructokinase can also be demonstrated in blood cells and ﬁbroblasts. Laboratory analysis may also show myogenic hyperuricaemia, due to metabolic shifting towards a non-glycolytic anaerobic pathway, which has by-products of uric acid and ammonia [60] . 5.4. Information & guidance for day-to-day management 5.4.1. Use of second-wind in GSD V It is essential that patients understand how to achieve ‘second-wind’ in order to improve physical activity tolerance and reduce muscle damage. The ‘second-wind’ phenomenon is speciﬁc to the muscles being used. Upon initiation of activity, patients with GSD V must go slow and pay attention to the following signals: muscle fatigue or pain, rate of perceived exertion, quickening heart rate and increased breathing effort. If any of these signals occur, patients are advised to slow down (reduce exertion) or pause until symptoms subside. This ‘slow-pause-resume’ pattern should be repeated as necessary until a marked improvement in physical activity tolerance is achieved. After 6–10 min, resting or stopping as necessary, aerobic metabolism becomes the dominant fuel source, and submaximal physical activity can be carried out more easily. If, however, the intensity of the activity increases (for example, walking uphill), there will be a deﬁcit in the immediate availability of substrates and symptoms will recur. At that time, the ‘slow-pause-resume’ pattern should be re-initiated. Patients with GSD VII are unable to metabolise blood glucose, and do not develop a ‘second-wind’ under conditions that produce one in patients with GSD V. Oxidative metabolism in patients with GSD VII is also substrate- limited, but the inability to utilise blood glucose as an oxidative fuel makes muscle oxidative capacity dependent upon the availability of fatty acids. The most dramatic change in exercise and oxidative capacity in these patients is a reduction in exercise capacity following a carbohydrate meal, a condition that has been dubbed the ‘out-of-wind’ effect [54] . It is advised that patients with GSD VII follow the same ‘slow-pause-resume’ pattern outlined for those with GSD V until warning signs subside and physical activity tolerance improves. 5.4.2. Physical activity - aerobic conditioning Aerobic conditioning is best reﬂected in ‘VO 2max ’; the maximal amount of oxygen that can be used during physical activity. The higher the value, the lower the risks of morbidity and mortality. Individuals with muscle GSDs tend to be in the range 15–30 ml/kg/min. Improving VO 2max by just 1 ml/kg/min results in a 10% decrease in morbidity. [ 61 , 62 ]. Individuals with GSD V or GSD VII should be undertaking some exercise aimed at improving CRF. The ‘right’ type of exercise can improve VO 2max . Individuals with a muscle GSD can only work at low to moderate intensity, ideally for at least 20 min, 2–4 times per week. See Supplementary Material - Appendix 3 5.4.3. Physical activity - strength training In the case of GSD V, strength training can increase muscle mass, lower the severity class, decrease baseline CK, and avoid ﬁxed muscle weakness. To avoid the risk of 1302

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Clinical Practice Guidelines for GSD V and VIIPage 10A. Lucia, A. Martinuzzi, G. Nogales-Gadea et al. Neuromuscular Disorders 31 (2021) 1296–1310 contractures, it is essential to adhere strictly to the guidelines. See Supplementary Material - Appendix 3 . The principle is a warm-up of all muscles into ‘second- wind’, followed by sets of very few repetitions using a circuit- training structure, rotating on multiple machines to give a recovery time of at least 3 min between sets. In the case of GSD VII, there is not adequate clinical data to recommend a strength-training programme for this cohort. 5.5. Dietary management 5.5.1. GSD V The beneﬁcial effects of intravenous glucose and oral sucrose supplementation on exercise capacity in people with GSD V are well established [ 4 , 48 , 63 , 64 ]. Oral sucrose shortly before strenuous exercise markedly improves exercise tolerance by providing a stable ﬂux of glucose to fuel the working muscles, independent of the blocked glycogen breakdown, with a blunting of the barrier to ‘second-wind’ as a result. Currently, the recommendation is to ingest 37 g of sucrose, which approximately corresponds to one can of soda (330 ml), 5–10 min before exercise [63] . Due to the risk of weight gai n and related health issues, use of this strategy must be carefully planned. Sucrose supplementation for individuals with diabetes must be closely supervised. The potential effects of repeated sucrose supplementation during prolonged exercise are currently being investigated and any recommendations regarding repeated supplementation must await the results of these investigations. A carbohydrate-rich diet has proven beneﬁcial compared to a protein-rich diet [65] . The theory is that the carbohydrate- rich diet maintains the hepatic glycogen stores, providing a more stable supply of glucose ﬂux from the liver to the muscle. However, the diet will not eliminate all GSD V symptoms and cannot abolish the barrier to ‘second- wind’, therefore the risk of muscle damage is still present. Furthermore, the speciﬁc diet composition and carbohydrate level needed is still unknown. Triheptanoin oil supplementation has been shown to be ineffective in people with GSD V, and is therefore not recommended as a dietary management strategy [52] . The low carbohydrate ketogenic diet (LCKD) is currently being investigated as a potential dietary management strategy. 5.5.2. GSD VII Dietary treatment in GSD VII has not been studied in any detail. In contrast to GSD V, oral or intravenous supplements with sucrose or glucose are detrimental for individuals with GSD VII, as glucose cannot be metabolised. Sucrose/glucose supplementation in GSD VII produces an ‘out-of-wind’ phenomenon, which is the opposite of the ‘second- wind’ phenomenon seen in GSD V with sucrose/glucose supplementation [6] . LCKD has shown long-term effects in one patient with GSD VII, with improved exercise tolerance and subjective alleviation of muscle symptoms during a 5- year follow-up period [66] . According to this study, a LCKD can potentially beneﬁt selected patients with GSD VII with proper medical and nutritional supervision. However, placebo- controlled studies with larger cohorts are warranted to provide conclusive evidence on composition and effects of this diet. 5.6. Cramps and contractures The exact underlying mechanism for muscle cramps is not fully understood. It begins with a nerve-activated muscle contraction. Some investigators suggest that hydrogen ion accumulation in the lumen of a blood vessel results in vasoconstriction, and downstream from that, the muscle tissue becomes partially ischaemic, which triggers cramping [67] . This can occur in any individual. Muscle contractures, which can be observed in patients with GSD V and those with GSD VII, are different from muscle cramps, because they are not elicited by the nerve, but by intrinsic mechanisms in the muscle itself. In consequence, contractures, unlike muscle cramps, are silent on electromyography. Contracture in GSD V and GSD VII is the response to impending muscle damage associated with the energy deﬁciency, and is longer lasting and generally more painful than muscle cramps. Muscles will generally recover following a cramp or contracture, but repeated episodes can accumulate muscle damage. To manage a cramp or contracture, cessation of the causal activity is recommended until pain resolves. Unlike stretching of muscle cramps, stretching of a muscle in contracture may cause further muscle damage, and should be avoided. 5.7. Pain management The primary goal in management of GSD V and GSD VII is to avoid excessive muscle breakdown. By doing so, the experience of pain is likely to be lessened. Individuals must learn how to recognise the interim warning signs of muscle fatigue and myalgia during the pre-‘second-wind’ period and respond accordingly. However, generally the pain from cramps is of short duration and should not prompt use of pain medications, as the pain often will be over by the time the pain medications start to work. Following intense aerobic and anaerobic activities (for example, carrying a heavy object or running for a bus), in which the metabolic demand on the muscle surpasses the ability of this tissue to produce energy fast enough, individuals may develop cramps, contractures, or worse, rhabdomyolysis. To manage episodic occurrences of cramps, paracetamol (acetaminophen) may be taken after activity has ceased. For more severe pain, which lasts for hours, patients may need to seek medical attention. For patients that experience chronic daily pain, a thorough assessment of their aerobic and muscle conditioning is warranted, as there is an inverse relationship between aerobic ﬁtness/muscle strength and chronic pain. Furthermore, chronic use of opioid medications is not recommended, as they may mask feedback from the muscles, leading to further muscle damage and recurring pain. Instituting a carefully planned 1303

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Neuromuscular Disorders 31 (2021) Page 11A. Lucia, A. Martinuzzi, G. Nogales-Gadea et al. Neuromuscular Disorders 31 (2021) 1296–1310 regular exercise programme should help to reduce chronic pain. Patients with GSD V or GSD VII can anticipate some muscle fatigue and pain, in GSD V especially pre-‘second- wind’. These sensations signify the need to respond and modify activity. However, in some cases, pain may not be related to having a muscle GSD, and therefore each complaint should be thoroughly assessed to determine the correct aetiology. 6. Medical emergencies Individuals with GSD V or GSD VII are at increased risk of rhabdomyolysis. All activity (including ADLs and formal exercise) can lead to muscle breakdown and the potential for rhabdomyolysis, the risk of which increases as the combined demand of intensity and duration of activity increases. While the occurrence is low, there is some potential for ARF and ACS subsequent to rhabdomyolysis [68] . The best prevention against rhabdomyolysis (as well as ARF and ACS) is to apply appropriate caution when engaging in all types of physical activity. This includes sporting activities and ADLs, particularly those involving high mechanical stress on low muscle mass (for example, handgrip and carrying or lifting heavy weights). It is recommended to gradually build up these types of activities (day by day, gently increasing loads). Carbohydrate ingestion (in the case of GSD V), together with abundant hydration before heavy and/or unaccustomed activity/exercise is recommended to prevent – or at least minimise – muscle damage. 6.1. Rhabdomyolysis Rhabdomyolysis – the breakdown of damaged skeletal muscle ﬁbres as reﬂected by the efﬂux of intracytoplasmic proteins such as CK and myoglobin into the bloodstream –is the main medical problem in GSD V and GSD VII. Myoglobinuria does not occur without rhabdomyolysis, but rhabdomyolysis does not necessarily result in visible myoglobinuria. Rhabdomyolysis can range from elevated CK to myoglobinuria, ACS or ARF (leading to heart failure, arrhythmias, electrolyte imbalance, and in severe cases, death) [69] . The symptoms of rhabdomyolysis vary individually, but may include myalgia, muscle weakness, nausea, vomiting, fever, myoglobinuria, oliguria, and anuria. In individuals with GSD V or GSD VII, the threshold for developing rhabdomyolysis is much lower than in unaffected individuals. Mechanical stress imposed by high muscle glycogen stores, down regulation of sodium–potassium pumps and oxidative stress all contribute to structural muscle ﬁbre fragility and membrane disruption, leading to an increase in serum CK [2] . Rhabdomyolysis is predominantly brought on by isometric exercise (for example, lifting weights) or intense ‘aerobic’ activity (for example, stair climbing or running) [18] . As is the case in healthy individuals, a number of factors can increase the risk of rhabdomyolysis in individuals with GSD V or GSD VII. Primary factors include individual CRF, and intensity, duration and type of activity (concentric, eccentric, isometric). Secondary factors include environmental temperature (heat), electrolyte imbalance, gender (male), and alcohol [69] . The primary treatment goal for rhabdomyolysis is to prevent the factors that lead to ARF. Discharge criteria are contingent upon a lack of myoglobinuria and a return to baseline renal function (creatinine and glomerular ﬁltration rate). 6.2. Acute renal failure Myoglobinuria due to rhabdomyolysis can produce ARF, but data from large cohorts of patients suggest that this emergency complication is a rare event in both GSD V and GSD VII. The mechanism of renal dysfunction is predominantly related to myoglobin-direct tubular cytotoxicity, vasoconstriction and tubular obstruction. Volume depletion enhances both vasoconstriction and the formation of obstructing casts. Patients with severe rhabdomyolysis should be treated with adequate ﬂuid administration to prevent renal impairment or be put on dialysis if warranted. However, it is important to take into account the ﬂuid balance to avoid further complications such as hypervolaemia and acute pulmonary oedema. For patients that develop ARF, consultation with nephrology is required. Standard criteria for dialysis initiation are: ﬂuid overload unresponsive to loop diuretics, and electrolyte disturbances such as hyperkalaemia, metabolic acidosis and uraemic encephalopathy. The levels of myoglobin and CK are not considered to be parameters upon which to base implementation of renal replacement therapy. To avoid episodes of myoglobinuria and so to reduce the risk of ARF, strenuous exercise should be avoided but regular moderate exercise can be beneﬁcial by improving CRF, and thus reducing symptoms. Although acute or chronic renal failure may present a problem, the occurrence of these conditions is quite rare, being reported in only 10 patients (6%) of a large Spanish cohort [18] , 5 patients (11%) of a British cohort [20] and 19 patients (7.9%) of the GSD V Euromac registry [53] . According to the literature, ARF is almost always reversible when emergency treatment is provided [26] . 6.3. Compartment Syndrome ACS is characterised by a rise in pressure within a closed fascial space in the absence of a traumatic event. This condition is rarely described in patients with GSD V [70] . In individuals with GSD V, severe sustained physical activity can lead to muscle contracture, thereby reducing blood ﬂow to contracting muscles, which may induce partial ischaemia. Potential development of a feedback loop between 1304

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Clinical Practice Guidelines for GSD V and VIIPage 12A. Lucia, A. Martinuzzi, G. Nogales-Gadea et al. Neuromuscular Disorders 31 (2021) 1296–1310 compartment oedema and decreased blood supply may predispose to compartment syndrome. ACS in the upper or lower limbs has been reported in individuals with GSD V following strenuous exercise, during the postpartum period, and in those who performed an ischaemic forearm test (no longer recommended) for GSD V diagnosis [71] . No associations of ACS and GSD VII are reported in the literature. ACS is a clinical diagnosis; the classic presentation is relentless pain not relieved by rest. Other signs include pallor, absence of pulse, paralysis and paraesthesia. Diagnosis may be supplemented using intracompartmental pressure measurements. Individuals with GSD V or GSD VII must be cautioned about the potential for ACS following strenuous activities. The use of continuous blood-pressure monitoring or compressive devices, as well as the use of tourniquets, are contraindicated in this patient population. Missed diagnosis of ACS may rapidly lead to irreversible muscle and nerve damage, resulting in musculotendinous contractures and sensorimotor deﬁcits. A prompt ACS diagnosis can be facilitated by using limb magnetic resonance imaging; this often leads to an expeditious surgical treatment with decompressive fasciotomies, which maximises functional outcomes for these patients [72] . 6.4. Haemolytic anaemia in GSD VII Muscle phosphofructokinase deﬁciency impairs the ability of erythrocytes to use carbohydrates as a bioenergetic substrate supply. Haemolysis can occur because of impaired adenosine-5  -triphosphate (ATP) generation and increased 2,3- bisphosphoglycerate generation from abnormal glycolysis, leading to problems with red blood cell membrane maintenance. Haemolytic anaemia (HA) can be present in GSD VII. In one apparent sub-type it is characterised by non-spherocytic HA without muscle symptoms. As a consequence of HA, myogenic hyperuricaemia results from an excessive degradation of muscle purine nucleotides, secondary to impaired ATP generation. This process is sustained by the inability of the kidneys to process an excess of uric acid due to myoglobin disposal. High levels of indirect bilirubin are often found in blood, as is a recurrent increase in reticulocytes . These are immature red blood cells produced by bone marrow, which is highly active in an attempt to replace red blood cell loss. 6.5. Rehabilitation protocol Once the patient has a clear reduction in clinical symptoms (for example weakness, swelling, and pain), their CK level is trending downward, and laboratory tests for kidney function are normal, discharge from hospital may be considered. There should be a discussion with the patient as to why the episode occurred. Particular consideration should be given to any physical activities or exercises which were unusually intense, of unusually long duration, or with which the patient was previously not familiar. The development of strategies to avoid such episodes in the future should be encouraged. Notably, gradual familiarisation should be encouraged with any new activities. There is currently no scientiﬁc evidence on how the patient should gradually and safely return to baseline ADL and exercise. As such, no speciﬁc rehabilitation protocol can be proposed based on published data. This being said, we propose that the patient should not return to normal activity levels until the CK values and pain/cramping have returned to their pre-episode baseline levels. In any event, this should not be in less than one week, bearing in mind that muscle regeneration usually begins during the ﬁrst week after injury and peaks at about two weeks [73] . Pain medication should be used sparingly throughout rehabilitation, so as not to mask the warning sign of pain, which is an evolutionarily conserved mechanism that ensures full restoration of biological homeostasis. Non-steroidal anti- inﬂammatory drugs (NSAIDs) are not recommended during recovery from ARF due to afferent artery vasoconstriction. In any case, physical activities should be limited to below the threshold of pain; for example, if ﬁtness permits, gentle cycling or walking can be undertaken at intensities that the patient knows are not going to trigger cramps. It is always good to stimulate muscle regeneration through an increased delivery of trophic factors via the bloodstream. 7. General medical care 7.1. Considerations for general practitioners Diagnosis and management should be provided by an experienced clinical team at a CoE. However, the GP can provide further support by sharing information about: (1) improving overall ﬁtness, (2) limiting anaerobic and static activities, (3) use of ‘second-wind’ (in the case of GSD V); (4) psychological impact and management thereof, (5) recognising symptom onset, and (6) the need for emergency care. The basal plasma CK level should be established as a reference point, and CK can then be further tested to aid in assessment of any episode of rhabdomyolysis. An elevated CK level is not an immediate alert for a cardiac event; it is preferable to rely on more speciﬁc cardiac tests. (Note that an increased troponin T level can also be present in some muscle disorders, possibly including GSD V and GSD VII.) The enzymes AST and ALT may be mildly increased due to skeletal muscle damage, rather than hepatic issues [74] . Further investigation is indicated if ALP or bilirubin levels are signiﬁcantly increased. Patients should be monitored for concomitant conditions. See Supplementary Material - Appendix 4 . Due to the restriction of blood ﬂow, blood-pressure cuffs can be damaging and should be removed as soon as possible. During routine examinations, the use and duration of positions in which a muscle is held in a static position, or muscles are 1305

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Neuromuscular Disorders 31 (2021) Page 13A. Lucia, A. Martinuzzi, G. Nogales-Gadea et al. Neuromuscular Disorders 31 (2021) 1296–1310 compressed, should be minimised, as a cramp or contracture may ensue. Given the interplay between the muscular and skeletal system, massage and chiropractic treatments may help to alleviate chronic pain. Therapists should be fully briefed on GSD V and GSD VII. Interventions should be mild and should avoid stressing the muscles so as not to cause defence contractions or damaging pressure. Patients should carry an emergency card or ‘in case of emergency’ (ICE) app on their smartphone to prompt them about when to seek medical assistance. If, after activity, they have one or more of: myoglobinuria, feeling very unwell with ﬂu-like symptoms, oliguria or anuria, muscle weakness, muscle swelling, and very severe myalgia, they should drink water at 2x maintenance and seek medical attention. 7.2. Concomitant conditions In addition to the typical muscle-related symptoms, there may be an increased prevalence of other conditions in patients with GSD V or GSD VII. Some conditions, such as gout are well documented in patients with GSD V, whereas others, such as ocular involvement in GSD V, are emerging. Supplementary Material - Appendix 4 provides an overview of established and emerging conditions across the following areas: cardiology, rheumatology, nephrology, psychology/psychiatry, endocrinology, ophthalmology and haematology. 7.3. Potential drug–disease interactions When prescribing medications for other conditions a check should be made for any side-effects or contraindications in skeletal muscle disorders. It is recommended that a baseline CK level is established before initiating treatment, so that any increase in CK level can be determined. Although statin medications are generally well tolerated, the most common side-effects relate to skeletal muscle – myalgia, myositis, and rhabdomyolysis [75] . Other cholesterol-lowering drugs may also worsen myopathy in patients with GSD V [76] . Use of systemic steroids may also increase the risk of myalgia and rhabdomyolysis. It is advisable to ‘start low and go slow’ when prescribing new medications. Most anaesthetists consider muscle glycogenosis no differently from other muscle diseases in which the potential risk of developing malignant hyperthermia (MH) mandates the use of special precautions in the choice of the anaesthetic and the use of muscle relaxants. However, there is no report in the literature of MH events in patients with GSD V or VII. Despite the lack of evidence for occurrence of MH in GSD V and GSD VII, most authors consider it advisable to apply the same precautions used for conditions prone to MH; that is, to avoid halogenated agents and depolarising relaxants such as succinylcholine, and to keep dantrolene sodium in the operating room [77] . This speciﬁc risk might be overestimated, even in the presence of a positive in vitro contracture test showing MH susceptibility [ 78 , 79 ]. Care should be taken with regard to the use of pain medications in patients with GSD V and GSD VII as these may mask the signals which patients need in order to adjust activity appropriately. 8. Surgery As outlined in Section 7.3 , anaesthetists should follow MH protocol in patients with GSD V or GSD VII. Hypoglycaemia, tourniquet use, prolonged forced position/compression, hypothermia and shivering are all conditions in which the metabolic block in GSD V and GSD VII might precipitate contractures and rhabdomyolysis in patients, possibly evolving into ARF. The key unifying element is the generalised or focal failure (for lack of supply or excessive use) of the readily available energy source provided to skeletal muscle by blood glucose. It is therefore advisable that patients meet the anaesthetist prior to major procedures to review the precautions detailed below. Recommended preventive measures include: the following of MH protocol; careful monitoring of body temperature (with the use of thermal blanket or warmed ﬂuids if needed); the use of a urinary catheter to enable immediate identiﬁcation of possible pigmenturia; the avoidance of tourniquets or continuous blood-pressure monitoring by brachial cuff; consideration of the positioning of the patient, especially during lengthy procedures, to avoid focal compression; measurement of blood glucose hourly during the procedure; and strict surveillance during the 24 h following a procedure (for example, monitoring of urine output and blood glucose). With these precautions in place, any scheduled surgery is not expected to present an excessive risk because of the diagnosis of GSD V or GSD VII. 9. Obstetric care The uterus is composed of smooth muscle, which has a different isoform of glycogen phosphorylase and is therefore not affected in female patients with GSD V. There is no published data on pregnancy and childbirth in these conditions, other than individual case reports. Of a cohort of 127 females with GSD V (125) or GSD VII (2), a retrospective review across the obstetric spectrum did not suggest that any particular problems had occurred, either in the antepartum/intrapartum or postpartum periods. Indeed, most women had their babies before the diagnosis of either GSD V or VII was made, and they had the same incidence of interventional delivery (forceps and caesarean section) as did the general population (16%) [Quinlivan, R., unpublished results]. Nevertheless, the strain and efforts associated with the intrapartum phase may pose a potential risk of muscle contractures or energetic crises. A careful exercise adaptation training programme may be advisable to minimise such risk. There are anecdotal reports of improved activity tolerance during pregnancy, possibly due to the peculiar hormonal status 1306

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Clinical Practice Guidelines for GSD V and VIIPage 14A. Lucia, A. Martinuzzi, G. Nogales-Gadea et al. Neuromuscular Disorders 31 (2021) 1296–1310 associated with it, and to the hyperglycaemia experienced by some pregnant women. In order to lessen potential muscle fatigue and cramps associated with newborn care, it is important for women with GSD V or GSD VII to exercise caution during unaccustomed tasks, such as carrying their newborn and frequent feeding. 10. Publications and resources A wide range of resources is available for patients and medical professionals. These include publications, web sites, videos, and courses. Details are available in Supplementary Material - Appendix 5 . 11. Emerging issues and knowledge gaps 11.1. Impact on carriers Some cases of ‘manifesting’ heterozygotes or carriers –individuals who show some symptoms characteristic of GSD V despite being carriers of only one pathogenic variant in the PYGM gene – have been reported, [80–86] but there is controversy, with misdiagnosis being a possibility. In a recent study, 50 GSD V carriers were assessed to see whether any were actually ‘manifesting’ heterozygotes of GSD V [87] . Only 14% of carriers manifested some activity- related muscle problems (for example, exacerbated myalgia or weakness), and when present muscle symptoms were milder than those commonly reported in patients. Of note, no carrier (manifesting or not) showed the ‘second-wind’ phenomenon or a ﬂat blood lactate response to maximal-intensity exercise, both of which are hallmarks of GSD V. 11.2. Third wind in GSD V? ‘Third wind’ was coined by individuals with GSD V who, from personal experience, suggested that after 2 h of walking there seems to be a further improvement in physical activity tolerance. Research conducted at Brunel University London was able to conﬁrm that ‘third wind’ is a real phenomenon in GSD V. Metabolism in individuals with GSD V appeared to be quite different from that of non-GSD V individuals, in whom prolonged exercise elicits a slow climb in the percentage of fat used as fuel. By contrast, those with GSD V had a long slow climb in the use of carbohydrate as fuel, suggesting a greater contribution from gluconeogenesis [88] . 11.3. LCKD in GSD V LCKD has shown promise as a treatment option for GSD V. A recent pilot study found that a modiﬁed ketogenic diet composed of a minimum of 75% fat and a maximum of 10% carbohydrates seemed to improve exercise capacity and improve GSD V-related symptoms [ 6 , 51 ]. This is in line with published case series [ 66 , 89 ], which also showed promising effects, and with patient experiences published in an IamGSD survey [90] . However, a randomised placebo-controlled trial is lacking, therefore the efﬁcacy of a LCKD in the treatment of GSD V has not been determined and cannot currently be recommended. Studies are currently ongoing in Copenhagen, London and Italy [91] . LCKD works by mimicking the physiological stage of fasting, in which low carbohydrate levels induce hormonal changes (lowering of insulin levels and increasing glucagon levels), stimulating fat oxidation and ketone body production. Ketone bodies (KB) constitute a desirable and fast-working energy source for both the brain and working muscles independent of glycogen breakdown. Thus, KB could be an alternative fuel source, especially during the ﬁrst critical minutes of exercise before ‘second-wind’ is achieved. Increased fat oxidation should in theory also beneﬁt people with GSD V, especially during prolonged exercise. 11.4. Cognitive impairment GSD V and GSD VII are considered to be rare diseases in which brain function is normally spared. GSD V has commonly been regarded as a ‘pure myopathy’. Nevertheless, myophosphorylase expression is not muscle-restricted. With regard to the brain, a deﬁciency of the brain isozyme of creatine kinase (CK-BB) in adults is complemented by an aliquot of the muscle isoform (CK-MM). Glycogen is the main energy reserve in the central nervous system (CNS) and accumulates predominantly in astrocytes, suggesting that the lack of myophosphorylase in the brain may impair its function. To date, the occurrence of CNS symptoms has rarely been reported in GSD V. Some years ago, a pilot study on neuropsychological performances in patients with GSD V showed that patients performed worse than unaffected individuals on tests of verbal ﬂuency and verbal memory [92] . Despite this, further studies would be necessary to establish if there is involvement of the brain in GSD V and GSD VII. IamGSD Study Group Deeksha Bali (Biochemical Genetics Laboratory, Duke Health, Durham, North Carolina, USA). Richard Godfrey (Department of Sport Health and Exercise Sciences, Brunel University, Uxbridge, UK). Ronald Haller (University of Texas, Southwestern Medical Center, Dallas, USA). Priya Kishnani (Department of Pediatrics, Duke University School of Medicine, Durham, USA). Pascal Laforêt (Neurology Department, Raymond-PoincaréTeaching Hospital, Garches, France). Nicoline Løkken (Copenhagen Neuromuscular Center, Rigshospitalet, Copenhagen, Denmark). Olimpia Musumeci (U.O.C. di Neurologia e Malattie Neuromuscolari, Dipartimento di Neuroscienze, Messina, Italy). Alfredo Santalla (Pablo de Olavide University, Seville, Spain). Mark Tarnopolsky (McMaster University, Health Sciences Centre, Toronto, Canada). 1307

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Neuromuscular Disorders 31 (2021) Page 15A. Lucia, A. Martinuzzi, G. Nogales-Gadea et al. Neuromuscular Disorders 31 (2021) 1296–1310 Antonio Toscano (U.O.C. di Neurologia e Malattie Neuromuscolari, Dipartimento di Neuroscienze, Messina, Ital). John Vissing (Copenhagen Neuromuscular Center, Rigshospitalet, Copenhagen, Denmark). Nicol Voermans (Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands). Andrew Wakelin (Association for Glycogen Storage Disease, UK). Acknowledgments The authors would like to acknowledge the Association for Glycogen Storage Disease US for initiating the project, the Association for Glycogen Storage Disease (UK), the International Association for Muscle Glycogen Storage Disease for information, Jeremy Michelson (Columbia University) for reviewing material related to GSD VII and ﬁnally Louise Tinsley and Barbara Reason for editing and proofreading. Disclosures Dr. Tarnopolsky is the founder and CEO of Exerkine Corporation and they (Exerkine) have ﬁled a patent on the use of a ketogenic compound for use in lysosomal storage diseases that could be potentially of beneﬁt in glycogen storage diseases Funding This work was supported by Reneo Pharmaceuticals Inc. and the International Association for Muscle Glycogen Storage Disease. Supplementary material Supplementary material associated with this article can be found, in the online version, at doi: 10.1016/j.nmd.2021.10. 006 . References [1] Llavero F, Sastre AA, Montoro ML, Gálvez P, Lacerda HM, Parada LA, et al. McArdle disease: new insights into its underlying molecular mechanisms. Int J Mol Sci 2019;20. doi: 10.3390/ijms20235919 . [2] Santalla A, Nogales-Gadea G, Ørtenblad N, Brull A, de Luna N, Pinós T, et al. McArdle disease: a unique study model in sports medicine. Sport Med 2014;44:1531–44. doi: 10.1007/ s40279- 014- 0223- 5 . [3] Hargreaves M, Spriet LL. 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Clinical Practice Guidelines for GSD V and VIIPage 16A. Lucia, A. Martinuzzi, G. Nogales-Gadea et al. Neuromuscular Disorders 31 (2021) 1296–1310 [28] Pérez M, Ruiz JR, Fernández del Valle M, Nogales-Gadea G, Andreu AL, Arenas J, et al. The second wind phenomenon in very young McArdle’s patients. Neuromuscul Disord 2009;19:403–5. doi: 10. 1016/j.nmd.2009.04.010. [29] Scalco RS, Morrow JM, Booth S, Chatﬁeld S, Godfrey R, Quinlivan R. Misdiagnosis is an important factor for diagnostic delay in McArdle disease. Neuromuscul Disord 2017;27:852–5. doi: 10.1016/j.nmd.2017. 04.013 . [30] Livingstone C, Al Riyami S, Wilkins P, Ferns GA. McArdle’s disease diagnosed following statin-induced myositis. Ann Clin Biochem 2004;41(4):338–40 PtPMID: 15298748. doi: 10.1258/ 0004563041201554. [31] García-Consuegra I, Asensio-Peña S, Ballester-Lopez A, Francisco- Velilla R, Pinos T, Pintos-Morell G, et al. Missense mutations have unexpected consequences: the McArdle disease paradigm. 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No spontaneous second wind in muscle phosphofructokinase deﬁciency. Neurology 2004;62:82–6. doi: 10.1212/ WNL.62.1.82. [55] Hogrel JY, Laforêt P, Ben Yaou R, Chevrot M, Eymard B, Lombès A. A non-ischemic forearm exercise test for the screening of patients with exercise intolerance. Neurology 2001;56:1733–8. doi: 10.1212/WNL.56. 12.1733 . [56] Drouet A, Zagnoli F, Fassier T, Rannou F, Baverel F, Piraud M, et al. Intolérance musculaire à l’effort par déﬁcit en phosphofructokinase: apport au diagnostic du bilan métabolique musculaire (tests d’effort, spectroscopie RMN du P31)) [Exercise-induced muscle pain due to phosphofrutokinase deﬁciency: diagnostic contribu. Rev Neurol 2013;169:613–24 (Paris). doi: 10.1016/j.neurol.2013.02.006 . [57] Aasly J, Va n Diggelen O P, Boer AM, Brønstad G. Phosphoglycerate kinase deﬁciency in two brothers with McArdle-like clinical symptoms. Eur J Neurol 2000;7:111–13. doi: 10.1046/j.1468-1331.2000.00012.x. [58] Vissing J, Haller RG. 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Neuromuscular Disorders 31 (2021) Page 17A. Lucia, A. Martinuzzi, G. Nogales-Gadea et al. Neuromuscular Disorders 31 (2021) 1296–1310 [66] Similä ME, Auranen M, Piirilä PL. Beneﬁcial effects of ketogenic diet on phosphofructokinase deﬁciency (Glycogen Storage Disease type VII). Front Neurol 2020;11:57. doi: 10.3389/fneur.2020.00057 . [67] Spurway N, Godfrey R, Cham C. Abstracts of the XIX European Conference on Muscle contraction and Cell Motility: relaxation of the vascular smooth muscle by organic bases applied at neutral pH. J Muscle Res Cell Motil 1991;12:93. doi: 10.1007/BF01781177 . [68] McMahon G, Zeng X, Waikar S. A risk prediction score for kidney failure or mortality in rhabdomyolysis. JAMA Intern Med 2013;173:1821–8. doi: 10.1001/JAMAINTERNMED.2013.9774. [69] Kim J, Lee J, Kim S, Ryu H Y, Cha KS, Sung DJ. Exercise-induced rhabdomyolysis mechanisms and prevention: a literature review. J Sport Heal Sci 2016;5:324–33. doi: 10.1016/j.jshs.2015.01.012. 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[75] Vladutiu GD, Simmons Z, Isackson PJ, Tarnopolsky M, Peltier WL, Barboi AC, et al. Genetic risk factors associated with lipid-lowering drug-induced myopathies. Muscle Nerve 2006;34:153–62. doi: 10.1002/ mus.20567 . [76] Perez-Calvo J, Civeira-Murillo F, Cabello A. Worsening myopathy associated with ezetimibe in a patient with McArdle disease [1]. QJM Mon J Assoc Phys 2005;98:461–2. doi: 10.1093/ qjmed/ hci074. [77] Quintero Salvago AV, Leal del Ojo del Ojo JD, Barrios Rodríguez L, Fedriani de Matos JJ, Morgado Muñoz I. Total thyroidectomies in patient with McArdle’s syndrome: anesthetic management. Rev Esp Anestesiol Reanim 2019;66:163–6. doi: 10.1016/j.redar.2018.10.004. [78] Bollig G, Mohr S, Ræder J. McArdle’s disease and anaesthesia: Case reports. Review of potential problems and association with malignant hyperthermia. Acta Anaesthesiol Scand 2005;49:1077–83. doi: 10.1111/ j.1399-6576.2005.00755.x. [79] Bollig G. 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Clinical Practice Guidelines for GSD V and VIIPage 18IamGSD would like to thank the authors and the other members of the team who made up the international study group which prepared these Clinical Practice Guidelines.Deeksha Bali Biochemical Genetics Laboratory, Duke Health, Durham, North Carolina, USA.Richard Godfrey Department of Sport Health and Exercise Sciences, Brunel University, Uxbridge, UK.Ronald Haller University of Texas, Southwestern Medical Center, Dallas, USA.Priya Kishnani Department of Pediatrics, Duke University School of Medicine, Durham, USA.Pascal Laforêt Neurology Department, Raymond-Poincaré Teaching Hospital, Garches, France.Nicoline Løkken Copenhagen Neuromuscular Center, Rigshospitalet, Copenhagen, Denmark.Alejandro Lucia Faculty of Sports Sciences, Universidad Europea de Madrid; Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES) and Research Institute of the Hospital 12 de Octubre (‘imas12’, PaHerg group), Madrid, Spain.Andrea Martinuzzi Conegliano Research Centre, IRCCS Eugenio Medea, Italy.Olimpia Musumeci U.O.C. di Neurologia e Malattie Neuromuscolari, Dipartimento di Neuroscienze, Messina, Italy.Gisela Nogales-Gadea Institut d’Investigació Germans Trias i Pujol, Camí de les Escoles, Barcelona, Spain.Ros Quinlivan MRC Centre for Neuromuscular Disease, National Hospital for Neurology and Neurosurgery, London, UK.Stacey Reason International Association for Muscle Glycogen Storage Disease, California, USA.Alfredo Santalla Pablo de Olavide University, Seville, Spain.Mark Tarnopolsky McMaster University, Health Sciences Centre, Toronto, Canada.Antonio Toscano U.O.C. di Neurologia e Malattie Neuromuscolari, Dipartimento di Neuroscienze, Messina, Italy.John Vissing Copenhagen Neuromuscular Center, Rigshospitalet, Copenhagen, Denmark.Nicol Voermans Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, e Netherlands.Andrew Wakelin Association for Glycogen Storage Disease, UK. IamGSD also thanks the many clinicians and researchers not listed above but who contributed to the many research papers in the references.

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Supplementary Material Page 21Clinical Practice Guidelines for GSD V and GSD VII – Supplementary MaterialAppendix 2 Clinical Variability Factors that may impact functional capacity Cardiorespiratory fitness (CRF) is an important determinant of the clinical course of GSD V and GSD VII. Affected individuals are advised to engage in regular exercise in order to improve CRF, which in turn can make activities of daily living (ADL) easier, improve health-related quality of life (HRQoL), and lessen the overall burden of GSD V and GSD VII. Unfortunately, many factors can influence the ability to achieve CRF. A review of all the factors that may influence physical activity tolerance is recommended for each individual. Author of this appendix Reason S, PhD, International Association for Muscle Glycogen Storage Disease (USA). October 2021 Page of 3 18•Access to care/information •Understand nuances (recognise second wind in GSD V)BARRIERS•Chronic disease (obesity, diabetes, etc.) •Acute disease •Muscle WastingCOMORBIDITIES•Current age •Late diagnosis •Support – family, peers, clinical, psychologicalPERSONAL•Other genetic mutations that impact physical activity tolerance •Disease modifying mutations (ACE genotypes, gender)GENETICS•Ambient temperature extremes (heat and cold) •Wind •Terrain / surfaceENVIRONMENT•Diet composition •Diet satisfaction •Diet complianceNUTRITION•Healthcare costs •Type of occupation (physical vs. sedentary)SOCIOECONOMIC•Frequency of regular exercise – aerobic & strength training •Aerobic capacity (VO2 max)PHYSICAL ACTIVITYPhysical Activity ToleranceFactors which may impact functional capacity in GSD V and VII.Variability factor Recommended actionSome examples include:Does not understand how to get into ‘second-wind’Demonstrate ‘second-wind’ using the 12-minute walk testBMI is >30 Discuss strategies (nutrition/exercise) to lower BMIDifficulties at work related to physical activity intoleranceEstablish reasonable modifications with employer

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Clinical Practice Guidelines for GSD V and VIIPage 22Clinical Practice Guidelines for GSD V and GSD VII – Supplementary MaterialAppendix 3 Physical Training Guidelines Aerobic and resistance training The energy crisis in GSD V and GSD VII The muscle glycogen storage diseases McArdle disease (GSD V) and Tarui disease (GSD VII) are rare metabolic myopathies caused by homozygous or compound heterozygous mutations in the PYGM and PFKM genes, respectively. In GSD V a lack of the enzyme myophosphorylase results in impairment of muscle glycogen breakdown (glycogenolysis), and in GSD VII there is a complete block in glycolysis in the muscle due to deficiency of the enzyme phosphofructokinase; both of these disorders result in a distinct energy crisis in skeletal muscle metabolism [3]. The primary issue for individuals with GSD V or GSD VII is managing muscle energy in order to lessen muscle fatigue, cramping, and pain during activities of daily living (ADL) and formal exercise. If physical activity is continued in spite of these symptoms, muscle damage may ensue, with the risk of exertional rhabdomyolysis, contracture and related adverse events. Page of October 20214 18Aerobic GlycolysisImmediate ATPAnaerobic Glycolysis'H¼FLHQWLQ0F$UGOH³VIURPJO\FRJHQANAEROBIC AEROBIC 2 seconds10% contributions to total10 seconds HoursMinutesCreatine PhosphateEnergy contribution to total effort at increasing durationSchematic representation of the percentage contribution of main energy sources for skeletal muscles during activity. The blue section represents the affected glycolytic system (glycogen) in patients with McArdle disease.

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Supplementary Material Page 23Clinical Practice Guidelines for GSD V and GSD VII – Supplementary MaterialExercise with GSD V and GSD VII Moderate aerobic exercise interventions for people with GSD V or GSD VII are beneficial and safe, and will improve aerobic endurance [4]. However, there are some rules to follow within the type of training. ● Patients with GSD V have severely limited adenosine-5′-triphosphate (ATP) resynthesis due to both the absence of glycogenolysis and limited mitochondrial oxidative phosphorylation because of reduced substrate availability. ● Patients with GSD VII cannot catalyse the conversion of fructose 6-phosphate to fructose 1,6-bisphosphate; accordingly, the use of both muscle glycogen and blood glucose is blocked. Thus, the exercise intolerance in patients with GSD V or GSD VII is caused by an imbalance between muscle energy demand and supply [3]. During high intensity aerobic and all anaerobic exercise, skeletal muscle is dependent upon glycolysis for energy. Hence, in these patients during short-term moderate-to-vigorous physical exertion, requiring anaerobic metabolism and a high glycolytic flux for oxidative combustion, an acute energy crisis occurs. Within the first minutes of exercise, and with increased intensity of ongoing exercise, unpleasant symptoms occur, which include tachycardia, severe muscle pain and fatigue. If exercise continues at the same intensity despite these symptoms, a muscle cramp occurs. This can result in severe muscle damage (rhabdomyolysis), leading to a contracture involving muscle tenderness, swelling and weakness. Rhabdomyolysis leads to the release of the muscle protein myoglobin, which is excreted through the kidneys, causing a reddish-brown discoloration of urine known as myoglobinuria. This can lead to acute renal failure, which may require dialysis and intensive care to reverse [4]. Patients with GSD V experience a ‘second-wind’, which is not shown to occur in those with GSD VII. If physical activity continues in a gentle manner, with the patient repeatedly slowing down or pausing when symptomatic, and then resuming activity once asymptomatic, after approximately 8-10 minutes the ‘second-wind’ phenomenon will occur. At this time symptoms will begin to subside and physical activity can be pursued more freely [6–9]. ‘Second-wind’ in GSD V occurs due to a change in the balance of muscle energy metabolism away from glycolysis and towards oxidative phosphorylation. This happens because of increased blood flow in the skeletal muscle, which enables the body to use alternative sources of energy (aerobic metabolism), such as glucose released from the liver glycogen store, and fatty acids, carbohydrate, and protein metabolism via mitochondrial respiration [6,10]. This metabolic shift enables individuals with GSD V to engage in submaximal physical activity with more normal muscle functioning. Physical activity in daily life In GSD V ‘second-wind’ is a useful tool that enables individuals to engage in activity/exercise with greater ease. However, this does not apply in GSD VII. The 8-10 minutes prior to achieving ‘second-wind’ presents a distinct challenge. Spontaneous movement is generally October 2021 Page of 5 18

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Supplementary Material Page 25Clinical Practice Guidelines for GSD V and GSD VII – Supplementary Materialwill have developed lipid metabolism and will become less dependent on this pre-exercise glucose ingestion. This glucose ingestion is contraindicated in patients GSD VII, as patients are shown to experience an ‘out-of-wind’ phenomenon [15,16]. Anaerobic exercise or static muscle contractions (for example, isometric contractions for a long time, such as planking or wall sit) should be avoided. If a patient with GSD V or GSD VII starts his or her training too quickly or too intensely (anaerobic), there is a risk of rhabdomyolysis. Aerobic training The following guideline is established for patients with GSD V. Those with GSD VII may be able to carefully follow the same guideline, with the exception of ‘second-wind’, although the low incidence of GSD VII means there is insufficient evidence to recommend it. Patients should start with a very light warm-up (for example, cycling at 30 RPM without resistance), during which the rating of perceived pain (RPP) should not exceed 3 (on a scale of 0 to 10, where 0 is no pain and 10 would be maximum pain). After achieving ‘second-wind’, moderate-intensity aerobic exercise applied gradually should help to improve muscle metabolism. During aerobic training (for example, brisk walking, cycling, swimming) the heart rate should ideally be between 50% and 75% of the maximum heart rate. The approximate maximum heart rate can be calculated using the Tanaka formula: 208 − (0.7 × age) [17]. Aerobic training intensity can also be controlled by a rating of perceived exertion (RPE), given the great sensitivity of muscle perception in these patients. Thus, 50–70% maximum heart rate is equivalent to an exercise intensity in which RPE is 5–7 (on a scale of 0 to 10, where 0 is no effort and 10 is maximum effort) with no pain, or at least minimal pain (RPP ≤ 1). The frequency of training should be between 2 and 4 times a week, for a minimum of 20 minutes up to a maximum of 1.5 hours. Aerobic adaptations are important to improve submaximal physical activity tolerance [13], and to ease the transition into ‘second-wind’ in ADLs (such as walking). In terms of adaptations, there is a dose effect; the more days and hours of aerobic training a week, the easier it will be to achieve ‘second-wind’ in ADLs. After a training session, light dynamic stretching and good hydration are recommended. Resistance exercise For GSD VII, the low incidence means that there is not adequate clinical data to recommend strength training. Strength training in patients with GSD V should be carried out on 2–3 non-consecutive days per week to achieve training adaptations (increase in muscle mass, changes to a lower severity class, decrease in baseline CK and absence of fixed muscle weakness) and must meet certain guidelines to avoid risk of contractures or rhabdomyolysis [3,18,19]. In addition to glycogen, another short burst of energy for high intensity exercise is provided via the phosphagen pathway (ATP–phosphocreatine system). This allows for anaerobic activities lasting up to 10 seconds at maximal exercise intensity [20,21]. The more October 2021 Page of 7 18

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Clinical Practice Guidelines for GSD V and VIIPage 26Clinical Practice Guidelines for GSD V and GSD VII – Supplementary Materialintense the exercise is, the faster the energy is consumed from the ATP–phosphocreatine system. It takes around 3 minutes to fully replenish this energy source [19]. As this metabolic pathway is not impaired in GSD V, patients may exercise safely when keeping within the ∼10 seconds of energy availability [3]. Therefore, for resistance or strength exercise, the 6-second rule applies; power efforts should not last longer than 6 seconds. After that, the creatine phosphate pool may become empty and the patient cannot switch to anaerobic metabolism. The ideal strength session structure would be: Warm-up: First, a small intake (~20–30 g) of simple carbohydrate (330 ml of conventional isotonic drink) [8,14] to improve glucose flow to the muscle. After 10–15 minutes walk/pedal for 12 minutes and then do 12 minutes of exercise in an arm-crank ergometer. This approach will trigger the occurrence of the ‘second-wind’ in both upper and lower body muscles. Strength training: Strength training must be carried out using equipment to exercise large muscle groups [18,19]. Sets of 6 repetitions are recommended to avoid depletion of the phosphagen deposits (and therefore avoid muscular crisis) [18,19]. It is recommended to gently stretch for 10–30 seconds after each set, to reduce stiffness [3,18,19]. It is important to follow a circuit training structure, rotating on multiple equipment to give a recovery time of Page of October 20218 18Structure of a strength training session. Adapted from [19].

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Clinical Practice Guidelines for GSD V and VIIPage 28Clinical Practice Guidelines for GSD V and GSD VII – Supplementary MaterialAppendix 4 Concomitant Conditions Established and emerging concomitant conditions In addition to the typical muscle-related symptoms, there may be an increased prevalence of other conditions in patients with GSD V or GSD VII. Some conditions, such as gout are well documented in patients with GSD V, whereas others, such as ocular involvement in GSD V, are emerging. This appendix provides an overview of established and emerging conditions. Cardiology GSD V is typically associated with an exaggerated cardiovascular response (tachycardia) to physical activity. There is a growing body of evidence associating GSD V with increased risk of coronary artery disease (CAD) manifesting as exertional angina [22] or cardiomyopathy with electrocardiogram (ECG) changes and focal areas of gadolinium enhancement at cardiac MRI [23,24]. The Euromac registry for muscle glycogenosis reports CAD in 8.3% of patients with GSD V [25]. The pathophysiology of the cardiac manifestation in GSD V is not fully understood. Cardiac muscle biopsy in patients with GSD V does not show any histologic abnormality and there is full expression of glycogen phosphorylase in its non-muscle-specific isoforms [22]. A tentative explanation relates the ischaemic heart disease to the strain imposed on the heart by the exaggerated cardiovascular response to exercise. Routine yearly ECG and, in the case of suspicion (especially in obese and hypertensive individuals), a cardiac MRI should be considered in the management of patients with GSD V. Cardiac involvement in GSD VII is reported at autopsy in 21% of cases with the systemic infantile form [26] and it is a relevant feature of the rodent model [27]. There is no extensive assessment of cardiac function in patients with GSD VII and therefore its relevance could be underestimated. One single Italian patient with GSD VII with unexplained hypertrophic cardiomyopathy has been reported [28]. No specific indications can therefore be provided regarding cardiac monitoring in GSD VII, but reporting of occasional concurrent cardiomyopathy and GSD VII is encouraged. The exercise stress test, usually requested when coronary pathology is suspected, should not be requested in muscle GSD patients due to the risk of muscle contracture. Monitoring the levels of cardiac troponins might offer a reliable alternative to exercise testing [29]. Rheumatology Gout arthritis, albeit rare, is the leading rheumatic co-morbidity in GSD VII, but is much less prevalent in GSD V [30,31]. Eight cases have been described in the literature, all of which are associated with the so-called “myogenic hyperuricaemia” [32]. Recurrence of gout in muscle GSD follows the known prevalence in middle-aged males (only one female patient Page of October 202110 18

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Supplementary Material Page 29Clinical Practice Guidelines for GSD V and GSD VII – Supplementary Materialwith GSD V and gout has been described). In many reported cases, the diagnosis of GSD V came years after the emergence of joint symptoms, and sometimes the typically elevated CK level was interpreted as a side effect of colchicine treatment. Gout or hyperuricaemia have been reported in 28 patients (11.7%) with GSD V in the Euromac registry [23]. Both disorders are associated with higher urate and ammonia production. The biochemical explanation probably lies in the increased clearance of adenosine monophosphate (AMP) through deamination to inosine monophosphate (IMP). AMP removal is needed to drive the condensation of 2 adenosine diphosphate (ADP) into adenosine triphosphate (ATP) + AMP to provide energy in acute anaerobic conditions [32]. Treatment with allopurinol or febuxostat is advised to control hyperuricaemia, whereas colchicine or anakinra have been used to treat arthritis. Urate kidney stones may occur in hyperuricaemic subjects and appropriate periodic non-invasive imaging (ultrasound) is warranted in these patients. Nephrology Acute renal failure is discussed in section 6.2 of the GSD V and GSD VII CPG. Even more rare is the occurrence of chronic renal failure (1%), mostly due to tubulointerstitial nephropathy secondary to repeated episodes of rhabdomyolysis. Intensivists and nephrologists caring for patients with acute or chronic kidney pathology should be alerted to the possible (or established) diagnosis of GSD V or GSD VII. Conversely, neurologists should consider monitoring renal function in patients with GSD V or GSD VII who present with recurrent myoglobinuria. There is no report of age-related decrease in renal function in GSD V or GSD VII. Psychology Psychiatric/psychological conditions are among the most frequent disorders misdiagnosed in patients with muscle GSD, especially in females with GSD V [33]. The psychological consequences of a missed or delayed diagnosis has not been investigated systematically. Three psychological phases can be described in patients with muscle GSD: pre-diagnosis, searching for a diagnosis, and post-diagnosis. Patients show similar strategies in the first two phases but differ in their coping style when facing the third [34]. The psychological profile of patients with muscle GSDs has been described mainly in relation to pain characteristics and coping strategies [35]. Pain is the most pervasive complaint of patients with GSD V or GSD VII. Both exercise-induced and permanent pain have been reported, with avoidance behaviour being the most frequent coping style. A significant gender difference was noted both in the prevalence of persistent pain and in coping strategies, with higher prevalence of permanent pain and pain-related endurance coping in females. Major depression is not a feature but mild depression can be detected in up to 30% of patients with GSD V [35]. Thirty-one percent of patients from a British cohort reported being treated at some time for anxiety, depression or bipolar disorders [36]. October 2021 Page of 11 18

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Clinical Practice Guidelines for GSD V and VIIPage 30Clinical Practice Guidelines for GSD V and GSD VII – Supplementary MaterialPsychiatric comorbidity in the Euromac GSD V cohort is found in 6.6% of patients, with depression and anxiety being most prevalent [25]. The systematic appraisal of the psychological profile should be part of the management for patients with muscle GSD. Endocrinology Diabetes (mainly type 2 diabetes (T2D)) and thyroid pathology (either thyrotoxicosis, hyper- or hypo-thyroidism, or cancer) are the most commonly reported endocrine comorbidities in GSD V. Abnormal glucose response and insulin resistance have been described both in the GSD V mouse model and in patients [37]. Increased glucose capture may represent an adaptive response of the muscle to facilitate glycolysis. Diabetes as a comorbidity with GSD V has been predominantly described in single patients [38,39], but a systematic search revealed a prevalence among patients with GSD V of 12% [40]. These prevalence rates are not higher than those reported for the general population in high- and middle-income countries [41]. Despite the lack of systematic information on the prevalence of diabetes in GSD VII, there is data that indicates that deficiency of PFKM subtype in humans may be associated with an impaired oscillatory insulin secretion pattern and insulin resistance [42,44]. Nevertheless, the description of T2D in GSD VII is limited to isolated cases [44,44]. Periodic monitoring of glycosylated haemoglobin levels should be included in follow-up care of patients with GSD V and those with GSD VII. The effect of a low carbohydrate diet in patients with both diabetes and GSD V might be an avenue to explore systematically. Similarly, as regular exercise is advised in patients with T2D [46] and aerobic exercise has been shown to be beneficial in GSD V and GSD VII, one can safely recommend regular mild aerobic exercise to patients with T2D and GSD V or GSD VII. More obscure is the mechanism underlying thyroid pathology (mostly hypothyroidism) in GSD V. Nine percent of patients with GSD V in the Euromac cohort reported some form of thyroid involvement [25]. Thyroid pathology is common in hepatic GSDs (types I, III, VI and IX), but it is not a known feature of muscle GSDs. More data are required to clarify this issue. Ophthalmology Ocular involvement in GSD V includes reported eyelid weakness resulting in epiphora and ectropion [47], but no further cases were reported. Ptosis has been reported [48] in 8 middle-aged Euromac registry patients (3.2%) [25]. More relevant clinically and scientifically is pattern dystrophy of the retinal pigment epithelium (RPE) [49–51]. This was interpreted as ‘double trouble’ or as the result of chromosome 11 defects extending to multiple genes. Five more cases have been described [53,53], in which complete evaluation (laser ophthalmoscopy, fundus autofluorescence, optical coherence tomography (OCT), OCT angiography, and electroretinograpy) was coupled with an extended search for mutations in genes associated with RPE (negative). In the recent cases, GSD V was confirmed by Page of October 202112 18

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Supplementary Material Page 31Clinical Practice Guidelines for GSD V and GSD VII – Supplementary Materialmolecular methods and the genotype in each case reflected the mutation frequency described in most GSD V cohorts (PYGM c148C>T). Almost all patients were 52 to 68 years old. An initial finding was some pattern-like lesions in RPE during routine funduscopy, but in most cases, the retinal abnormalities (perimacular yellow flecks) were associated with decreased vision (down to 20/80). The findings include hyperreflective deposits in the subretinal space, abnormal OCT, and atrophy or even absence of the ellipsoid zone. The pathophysiology is still unknown. Glycogen is found in the rods and the cones, together with glycogen synthase and phosphorylase. In human RPE the brain and the muscle isoforms of glycogen phosphorylase are expressed [54]. A hypothesis calls for a defect in glycogenolysis within the high-energy requiring RPE, causing failure of energy production and glycogen storage. A differential expression of the two glycogen phosphorylase isoforms in rods and cones, as described in the mouse [55] could explain the selective involvement of the macular area. Less understandable is the asymmetry of the disease and the late progressive nature of the defect. In one case a single injection of anti-VEGF (ranibizumab 0.5mg/0.05ml) was followed by complete resolution of symptoms and retinal lesions in 2 months [50]. In adult patients with GSD V a funduscopy evaluation is warranted. If abnormalities are detected, laser ophthalmoscopy, fundus autofluorescence and OCT should be performed. Yearly follow up is advisable. Weakness or fatigue in specific muscles (for example, the levator palpebrae or inspiratory muscles) can lead to peculiar complaints (for example, ptosis or unexplained dyspnoea) and can lead to patients seeking help from ophthalmologists or pneumologists. Clinicians should be aware that focal presentation of exertional or fixed weakness might be the manifestation of a metabolic muscle disorder. Haematology Haemolytic Anaemia (HA) is a form of anaemia due to haemolysis, an abnormal breakdown of red blood cells in blood vessels (intravascular haemolysis) or in other organs (extravascular). Among the clinical conditions characterised by HA and myopathies, it is important to avoid misdiagnosis. For this purpose, the role of the haematologist is relevant. The contemporary presence of HA, hyperuricaemia, hyperbilirubinaemia and increased reticulocytosis is highly suggestive of a genetic metabolic disorder involving blood and skeletal muscle. Bearing in mind these clues, PFK deficiency is the major candidate. Authors of this appendix Martinuzzi A, MD PhD (a), Reason S, PhD (b). (a) Istituto di Ricovero e Cura a Carattere Scientifico Eugenio Medea-Associazione “La Nostra Famiglia”, Italy. (b) International Association for Muscle Glycogen Storage Disease (USA). October 2021 Page of 13 18

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Clinical Practice Guidelines for GSD V and VIIPage 32Clinical Practice Guidelines for GSD V and GSD VII – Supplementary MaterialAppendix 5 Publications and Resources Useful resources for medical professionals and patients Links to most of these publications and other resources can be found at: www.iamgsd.org Resource Title Audience/s DescriptionPaperback books101 Tips for a Good Life with McArdle’s1) Patients An illustrated guide to managing the disease day-to-day. Euromac editions available in multiple languages. Wakelin A, 2012. 164pp.The McArdle Disease Handbook1) Patients 2) Medical professionalsPlain English guide to the scientific and medical research on the disease, with reference to over 250 original papers. Birch K, 2011. 208pp. Also in German and Italian.One Step at a Time1) Patients An account of a group of people with GSD V on a 32-day walk across Wales and what they learnt. Reason SL, 2013. 96pp.Booklets McArdle Disease Medical Overview1) GPs and other professionals 2) PatientsA general introduction to the condition. An essential guide for general practitioners supporting patients with GSD V (McArdle disease). Euromac editions available in 8 languages. Wakelin A, 2014-2020. 18pp.Living with McArdle Disease1) Patients In-depth patient’s guide to protecting themselves, starting an exercise programme and improving their techniques. Wakelin A,(online edition). 50pp.Leaflets At Home with McArdle’s1) Friends and family of patientsA guide to GSD V to help family and friends to understand and support the affected person. IamGSD, 2017. 6pp. English, German and French.At Work with McArdle’s1) Employer 2) PatientsA guide to GSD V to help family and friends to understand and support the affected person. IamGSD, 2017. 4pp. English, German and French.At School with McArdle’s1) Teachers and schoolsA guide to GSD V and how to accommodate and support affected pupils. IamGSD, 2016. 6pp. English, German and French.Card Information/ emergency card1) Patients Pocket information card for patients with GSD V who need help or who require assistance to decide whether they need medical attention. 4 pages. Available in 8 languages. (GSD VII card in English only.)Page of October 202114 18

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Supplementary Material Page 33Clinical Practice Guidelines for GSD V and GSD VII – Supplementary Material† Some national GSD support groups also offer Facebook groups in their languages and useful resources through their websites. Authors of this appendix Wakelin A (a), Reason S, PhD (b). (a) Association for Glycogen Storage Disease, UK. (b) International Association for Muscle Glycogen Storage Disease (USA). Websites † IamGSD 1) Patients 2) Medical professionalsDetailed information about GSD V (McArdle disease), GSD VII (Tarui disease) and other Muscle GSDs. www.iamgsd.org. Automated translation into 100 languages.Euromac Registry 1) Medical professionals 2) PatientsInformation about the Euromac Registry for people with GSD V (McArdle disease) and other very rare muscle GSDs. www.euromacregistry.euVideos Youtube channel: “IamGSD videos”1) Patients Video tips and some introductions to GSD V (McArdle disease); some have versions with subtitles in several languages. From IamGSD.Youtube channel: “GSD Screen”1) Patients Videos of patient stories, talks presentations about GSD V (McArdle disease), and other GSDs. From AGSD-UK.Euromac registry 1) Medical professionalsAn introduction to the work of the Euromac Registry. Euromac, 2011. Search Youtube for Euromac Registry.McArdle Disease & Euromac1) Medical professionalsA conference overview of GSD V (McArdle disease) and Euromac. Quinlivan R, 2014. www.youtube.com/watch?v=kSgyEK1w-d8Online support †Facebook groups 1) Patients A range of private groups managed by IamGSD for patients and parents to exchange experiences and support. See details on IamGSD website: www.iamgsd.orgCourses The McArdle’s Experience1) Patients 7-day residential courses for people with GSD V (McArdle disease) and GSD VII (Tarui disease). Details from AGSD-UK and IamGSD.October 2021 Page of 15 18

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Clinical Practice Guidelines for GSD V and VIIPage 34Clinical Practice Guidelines for GSD V and GSD VII – Supplementary MaterialReferences For these appendices [1] Baker JS, McCormick MC, Robergs RA. Interaction among Skeletal Muscle Metabolic Energy Systems during Intense Exercise. J Nutr Metab 2010;2010:905612. https://doi.org/10.1155/2010/905612. [2] Grehl T, Müller K, Vorgerd M, Tegenthoff M, Malin JP, Zange J. Impaired aerobic glycolysis in muscle phosphofructokinase deficiency results in biphasic post-exercise phosphocreatine recovery in 31P magnetic resonance spectroscopy. Neuromuscul Disord 1998;8(7):480-8. https://doi.org/10.1016/s0960-8966(98)00066-2. [3] Pietrusz A, Scalco RS, Quinlivan R. Resistance Exercise Training in McArdle Disease: Myth or Reality? Case Rep Neurol Med 2018;2018:1–6. https://doi.org/10.1155/2018/9658251. [4] Quinlivan R, Vissing J, Hilton-Jones D, Buckley J. Physical training for McArdle disease. Cochrane Database Syst Rev 2011. https://doi.org/10.1002/14651858.cd007931.pub2. [5] Kitaoka Y. McArdle disease and exercise physiology. Biology (Basel) 2014;3:157–66. https://doi.org/10.3390/biology3010157. [6] Braakhekke JP, De Bruin MI, Stegeman DF, Wevers RA, Binkhorst RA, Joosten EMG. The second wind phenomenon in mcardle’s disease. Brain 1986;109:1087–101. https://doi.org/10.1093/brain/109.6.1087. [7] Haller RG. Treatment of McArdle disease. Arch Neurol 2000;57:923–4. https://doi.org/10.1001/archneur.57.7.923. [8] Vissing J, Haller R. The effect of oral sucrose on exercise tolerance in patients with McArdle’s disease. N Engl J Med 2003;349:2503–9. https://doi.org/10.1056/nejmoa031836. [9] Vissing J, Haller RG. A diagnostic cycle test for McArdle’s disease. Ann Neurol 2003;54:539–42. https://doi.org/10.1002/ana.10725. [10] Santalla A, Nogales-Gadea G, Ørtenblad N, Brull A, de Luna N, Pinós T, et al. McArdle Disease: A Unique Study Model in Sports Medicine. Sport Med 2014;44:1531–44. https://doi.org/10.1007/s40279-014-0223-5. [11] Haller RG, Wyrick P, Taivassalo T, Vissing J. Aerobic conditioning: An effective therapy in McArdle’s disease. Ann Neurol 2006;59:922–8. https://doi.org/10.1002/ana.20881. [12] Maté-Muñoz JL, Moran M, Pérez M, Chamorro-Viña C, Gómez-Gallego F, Santiago C, et al. Favorable responses to acute and chronic exercise in McArdle patients. Clin J Sport Med 2007;17:297–303. https://doi.org/10.1097/JSM.0b013e3180f6168c. [13] Porcelli S, Marzorati M, Morandi L, Grassi B. Home-based aerobic exercise training improves skeletal muscle oxidative metabolism in patients with metabolic myopathies. J Appl Physiol 2016;121:699–708. https://doi.org/10.1152/japplphysiol.00885.2015. [14] Nogales-Gadea G, Santalla A, Ballester-Lopez A, Arenas J, Martín MA, Godfrey R, et al. Exercise and preexercise nutrition as treatment for McArdle disease. Med Sci Sports Exerc 2016;48:673–9. https://doi.org/10.1249/MSS.0000000000000812. [15] Haller R, Vissing J. No spontaneous second wind in muscle phosphofructokinase deficiency. Neurology 2004;62:82–6. https://doi.org/10.1212/WNL.62.1.82. [16] Haller RG, Lewis SF. Glucose-Induced Exertional Fatigue in Muscle Phosphofructokinase Deficiency. N Engl J Med 1991;324:364–9. https://doi.org/10.1056/nejm199102073240603. [17] Tanaka H, Monahan KD, Seals DR. Age-predicted maximal heart rate revisited. J Am Coll Cardiol 2001;37:153–6. https://doi.org/10.1016/S0735-1097(00)01054-8. [18] García-Benítez S, Fleck SJ, Naclerio F, Martín MA, Lucia A. Resistance (weight lifting) training in an adolescent with McArdle disease. J Child Neurol 2013;28:802–5. https://doi.org/10.1177/0883073812451328. [19] Santalla A, Munguía-Izquierdo D, Brea-Alejo L, Pagola-Aldazábal I, Díez-Bermejo J, Fleck SJ, et al. Feasibility of resistance training in adult McArdle patients: Clinical outcomes and muscle strength and mass benefits. Front Aging Neurosci 2014;6. https://doi.org/10.3389/fnagi.2014.00334. [20] Baker JS, McCormick MC, Robergs RA. Interaction among skeletal muscle metabolic energy systems during intense exercise. J Nutr Metab 2010;2010:905612. https://doi.org/10.1155/2010/905612. [21] Bogdanis GC, Nevill ME, Boobis LH, Lakomy HKA. Contribution of phosphocreatine and aerobic metabolism to energy supply during repeated sprint exercise. J Appl Physiol 1996;80:876–84. https://doi.org/10.1152/jappl.1996.80.3.876. [22] Nicholls DP, Campbell NPS, Stevenson HP, Patterson VH. Angina in McArdle’s disease. Heart 1996;76:372–3. https://doi.org/10.1136/hrt.76.4.372. [23] Moustafa S, Patton DJ, Connelly MS. Unforeseen cardiac involvement in mcardle’s disease. Hear Lung Circ 2013;22:769–71. https://doi.org/10.1016/j.hlc.2012.12.004. Page of October 202116 18

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Supplementary Material Page 35Clinical Practice Guidelines for GSD V and GSD VII – Supplementary Material[24] Jones DM, Lopes L, Quinlivan R, Elliott PM, Khanji MY. Cardiac manifestations of McArdle disease. Eur Heart J 2019;40:397. https://doi.org/10.1093/eurheartj/ehy783. [25] Scalco RS, Lucia A, Santalla A, Martinuzzi A, Vavla M, Reni G, et al. Data from the European registry for patients with McArdle disease and other muscle glycogenoses (Euromac). Orphanet J Rare Dis 2020;15:1–8. https://doi.org/10.1186/s13023-020-01562-x. [26] Wu P, Yang Y, Tey S, Yang C, Yang S, Lin C. Infantile form of muscle phosphofructokinase deficiency in a premature neonate. Pediatr Int 2015;57:746–9. https://doi.org/10.1111/PED.12616. [27] García M, Pujol A, Ruzo A, Riu E, Ruberte J, Arbós A, et al. Phosphofructo-1-kinase deficiency leads to a severe cardiac and hematological disorder in addition to skeletal muscle glycogenosis. PLoS Genet 2009;5. https://doi.org/10.1371/journal.pgen.1000615. [28] Musumeci O, Bruno C, Mongini T, Rodolico C, Aguennouz M, Barca E, et al. Clinical features and new molecular findings in muscle phosphofructokinase deficiency (GSD type VII). Neuromuscul Disord 2012;22:325–30. https://doi.org/10.1016/j.nmd.2011.10.022. [29] Chapman AR, Lee KK, McAllister DA, Cullen L, Greenslade JH, Parsonage W, et al. Association of high-sensitivity cardiac troponin I concentration with cardiac outcomes in patients with suspected acute coronary syndrome. JAMA - J Am Med Assoc 2017;318:1913–24. https://doi.org/10.1001/jama.2017.17488. [30] Puig JG, de Miguel E, Mateos FA, Miranda ME, Romera NM, Espinosa A, et al. McArdle’s disease and gout. Muscle Nerve 1992;15:822–8. https://doi.org/10.1002/mus.880150711. [31] Üsküdar Cansu D, Erdoğan B, Korkmaz C. Can hyperuricemia predict glycogen storage disease (McArdle’s disease) in rheumatology practice? (Myogenic hyperuricemia). Clin Rheumatol 2019;38:2941–8. https://doi.org/10.1007/s10067-019-04572-8. [32] Mineo I, Kono N, Hara N, Shimizu T, Yamada Y, Kawachi M, et al. Myogenic Hyperuricemia. A common pathophysiologic feature of glycogenosis types III, V, and VII. N Engl J Med 1987;317:75–80. https://doi.org/10.1056/NEJM198707093170203. [33] Scalco RS, Morrow JM, Booth S, Chatfield S, Godfrey R, Quinlivan R. Misdiagnosis is an important factor for diagnostic delay in McArdle disease. Neuromuscul Disord 2017;27:852–5. https://doi.org/10.1016/j.nmd.2017.04.013. [34] Russo E, Berto D, Vavla M, Carraro E, Trevisi E, Martinuzzi A. Psychological profile in McArdle’s patients. Abstract in PROCEEDINGS of the XVI CONGRESS OF THE ITALIAN SOCIETY OF MYOLOGY Lecce, Italy June 8-11, 2016. Acta Myol 2016;35:66-undefined. [35] Rommel O, Kley RA, Dekomien G, Epplen JT, Vorgerd M, Hasenbring M. Muscle pain in myophosphorylase deficiency (McArdle’s disease): The role of gender, genotype, and pain-related coping. Pain 2006;124:295–304. https://doi.org/10.1016/j.pain.2006.04.017. [36] Quinlivan R, Buckley J, James M, Twist A, Ball S, Duno M, et al. McArdle disease: A clinical review. J Neurol Neurosurg Psychiatry 2010;81:1182–8. https://doi.org/10.1136/jnnp.2009.195040. [37] Krag TO, Pinós T, Nielsen TL, Duran J, García-Rocha M, Andreu AL, et al. Differential glucose metabolism in mice and humans affected by McArdle disease. Am J Physiol - Regul Integr Comp Physiol 2016;311:R307–14. https://doi.org/10.1152/ajpregu.00489.2015. [38] Yamauchi A, Amano K, Ichikawa Y, Nakamoto S, Takei I, Maruyama H, et al. McArdle’s disease with non-insulin-dependent diabetes mellitus: The beneficial effects of hyperglycemia and hyperinsulinemia for exercise intolerance. Intern Med 1996;35:403–6. https://doi.org/10.2169/internalmedicine.35.403. [39] Ugur K, Aydogan Y, Akgun A, Aydin S. A High Creatine Kinase Concentration Might Be a Sign of McArdle Disease in Patient With Type 1 Diabetes. Biochem Insights 2019;12:117862641986140. https://doi.org/10.1177/1178626419861407. [40] Lucia A, Ruiz JR, Santalla A, Nogales-Gadea G, Rubio JC, García-Consuegra I, et al. Genotypic and phenotypic features of McArdle disease: Insights from the Spanish national registry. J Neurol Neurosurg Psychiatry 2012;83:322–8. https://doi.org/10.1136/jnnp-2011-301593. [41] Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus - Present and future perspectives. Nat Rev Endocrinol 2012;8:228–36. https://doi.org/10.1038/nrendo.2011.183. [42] Ristow M, Vorgerd M, Möhlig M, Schatz H, Pfeiffer A. Deficiency of phosphofructo-1-kinase/muscle subtype in humans impairs insulin secretion and causes insulin resistance. J Clin Invest 1997;100:2833–41. https://doi.org/10.1172/JCI119831. [43] Ristow M, Carlqvist H, Hebinck J, Vorgerd M, Krone W, Pfeiffer A, et al. Deficiency of phosphofructo-1-kinase/muscle subtype in humans is associated with impairment of insulin secretory oscillations. Diabetes 1999;48:1557–61. https://doi.org/10.2337/DIABETES.48.8.1557. October 2021 Page of 17 18

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Clinical Practice Guidelines for GSD V and VIIPage 36Clinical Practice Guidelines for GSD V and GSD VII – Supplementary Material[44] Danon MJ, Carpenter S, Manaligod JR, Schliselfeld LH. Fatal infantile glycogen storage disease: Deficiency of phosphofructokinase and phosphorylase b kinase. Neurology 1981;31:1303–7. https://doi.org/10.1212/wnl.31.10.1303. [45] Sivakumar K, Vasconcelos O, Goldfarb L, Dalakas M. Late-onset muscle weakness in partial phosphofructokinase deficiency: a unique myopathy with vacuoles, abnormal mitochondria, and absence of the common exon 5/intron 5 junction point mutation. Neurology 1996;46:1337–42. https://doi.org/10.1212/WNL.46.5.1337. [46] Yang Z, Scott CA, Mao C, Tang J, Farmer AJ. Resistance exercise versus aerobic exercise for type 2 diabetes: A systematic review and meta-analysis. Sport Med 2014;44:487–99. https://doi.org/10.1007/s40279-013-0128-8. [47] Lawrence W, Hagstrom W, Parsons R. Ectropion and epiphora in McArdle’s syndrome. Ann Plast Surg 1984;12:284–6. https://doi.org/10.1097/00000637-198403000-00012. [48] Chéraud C, Froissart R, Lannes B, Echaniz-Laguna A. Novel variant in the PYGM gene causing late-onset limb-girdle myopathy, ptosis, and camptocormia. Muscle and Nerve 2018;57:157–60. https://doi.org/10.1002/mus.25588. [49] Leonardy NJ, Harbin RL, Sternberg P. Pattern dystrophy of the retinal pigment epithelium in a patient with McArdle’s disease. Am J Ophthalmol 1988;106:741–2. https://doi.org/10.1016/0002-9394(88)90713-1. [50] Casalino G, Chan W, McAvoy C, Coppola M, Bandello F, Bird AC, et al. Multimodal imaging of posterior ocular involvement in McArdle’s disease. Clin Exp Optom 2018;101:412–5. https://doi.org/10.1111/cxo.12635. [51] Alsberge JB, Chen JJ, Zaidi AA, Fu AD. Retinal Dystrophy in a patient with McArdle disease. Retin Cases Brief Rep 2021;15:299–301. https://doi.org/10.1097/ICB.0000000000000790. [52] Mahroo OA, Khan KN, Wright G, Ockrim Z, Scalco RS, Robson AG, et al. Retinopathy Associated with Biallelic Mutations in PYGM (McArdle Disease). Ophthalmology 2019;126:320–2. https://doi.org/10.1016/j.ophtha.2018.09.013. [53] Vaclavik V, Naderi F, Schaller A, Escher P. Longitudinal case study and phenotypic multimodal characterization of McArdle disease-linked retinopathy: insight into pathomechanisms. Https://DoiOrg/101080/1381681020201727536 2020;41:73–8. https://doi.org/10.1080/13816810.2020.1727536. [54] Hernández C, Garcia-Ramírez M, García-Rocha M, Saez-López C, Valverde ÁM, Guinovart JJ, et al. Glycogen storage in the human retinal pigment epithelium: A comparative study of diabetic and non-diabetic donors. Acta Diabetol 2014;51:543–52. https://doi.org/10.1007/s00592-013-0549-8. [55] Haverkamp S, Wässle H, Duebel J, Kuner T, Augustine GJ, Feng G, et al. The Primordial, Blue-Cone Color System of the Mouse Retina. J Neurosci 2005;25:5438–45. https://doi.org/10.1523/JNEUROSCI.1117-05.2005. Page of October 202118 18IamGSD is working to enhance the quality of life of people affected by muscle glycogen storage disease. It aims to connect, educate and support patients, clinicians and researchers across all borders.Clinical Practice Guidelines for GSD V and GSD VII – Supplementary Material[44] Danon MJ, Carpenter S, Manaligod JR, Schliselfeld LH. Fatal infantile glycogen storage disease: Deficiency of phosphofructokinase and phosphorylase b kinase. Neurology 1981;31:1303–7. https://doi.org/10.1212/wnl.31.10.1303. [45] Sivakumar K, Vasconcelos O, Goldfarb L, Dalakas M. Late-onset muscle weakness in partial phosphofructokinase deficiency: a unique myopathy with vacuoles, abnormal mitochondria, and absence of the common exon 5/intron 5 junction point mutation. Neurology 1996;46:1337–42. https://doi.org/10.1212/WNL.46.5.1337. [46] Yang Z, Scott CA, Mao C, Tang J, Farmer AJ. Resistance exercise versus aerobic exercise for type 2 diabetes: A systematic review and meta-analysis. Sport Med 2014;44:487–99. https://doi.org/10.1007/s40279-013-0128-8. [47] Lawrence W, Hagstrom W, Parsons R. Ectropion and epiphora in McArdle’s syndrome. Ann Plast Surg 1984;12:284–6. https://doi.org/10.1097/00000637-198403000-00012. [48] Chéraud C, Froissart R, Lannes B, Echaniz-Laguna A. Novel variant in the PYGM gene causing late-onset limb-girdle myopathy, ptosis, and camptocormia. Muscle and Nerve 2018;57:157–60. https://doi.org/10.1002/mus.25588. [49] Leonardy NJ, Harbin RL, Sternberg P. Pattern dystrophy of the retinal pigment epithelium in a patient with McArdle’s disease. Am J Ophthalmol 1988;106:741–2. https://doi.org/10.1016/0002-9394(88)90713-1. [50] Casalino G, Chan W, McAvoy C, Coppola M, Bandello F, Bird AC, et al. Multimodal imaging of posterior ocular involvement in McArdle’s disease. Clin Exp Optom 2018;101:412–5. https://doi.org/10.1111/cxo.12635. [51] Alsberge JB, Chen JJ, Zaidi AA, Fu AD. Retinal Dystrophy in a patient with McArdle disease. Retin Cases Brief Rep 2021;15:299–301. https://doi.org/10.1097/ICB.0000000000000790. [52] Mahroo OA, Khan KN, Wright G, Ockrim Z, Scalco RS, Robson AG, et al. Retinopathy Associated with Biallelic Mutations in PYGM (McArdle Disease). Ophthalmology 2019;126:320–2. https://doi.org/10.1016/j.ophtha.2018.09.013. [53] Vaclavik V, Naderi F, Schaller A, Escher P. Longitudinal case study and phenotypic multimodal characterization of McArdle disease-linked retinopathy: insight into pathomechanisms. Https://DoiOrg/101080/1381681020201727536 2020;41:73–8. https://doi.org/10.1080/13816810.2020.1727536. [54] Hernández C, Garcia-Ramírez M, García-Rocha M, Saez-López C, Valverde ÁM, Guinovart JJ, et al. Glycogen storage in the human retinal pigment epithelium: A comparative study of diabetic and non-diabetic donors. Acta Diabetol 2014;51:543–52. https://doi.org/10.1007/s00592-013-0549-8. [55] Haverkamp S, Wässle H, Duebel J, Kuner T, Augustine GJ, Feng G, et al. The Primordial, Blue-Cone Color System of the Mouse Retina. J Neurosci 2005;25:5438–45. https://doi.org/10.1523/JNEUROSCI.1117-05.2005. Page of October 202118 18IamGSD is working to enhance the quality of life of people affected by muscle glycogen storage disease. It aims to connect, educate and support patients, clinicians and researchers across all borders.

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