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Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Quinlivan R, Martinuzzi A, Schoser B This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2010, Issue 12 http://www.thecochranelibrary.com Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . WHAT’S NEW . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 2 2 3 3 4 6 9 12 13 13 15 27 27 28 28 28 29 29 29 29 i [Intervention Review] Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) Rosaline Quinlivan1 , Andrea Martinuzzi2 , Benedikt Schoser3 1 MRC Centre for Neuromuscular Diseases and Dubowitz Neuromuscular Centre, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery and Great Ormond Street, London, UK. 2 The Conegliano-Pieve Research Centre, Medea Scientific Institute, Conegliano, Italy. 3 Department of Neurology, Friedrich-Baur Institute Ludwig-Maximilians University Munich, D-80336 Munich, Germany Contact address: Rosaline Quinlivan, MRC Centre for Neuromuscular Diseases and Dubowitz Neuromuscular Centre, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery and Great Ormond Street, PO Box 114, London, WC1B 3BN, UK. [email protected]. Editorial group: Cochrane Neuromuscular Disease Group. Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 12, 2010. Review content assessed as up-to-date: 17 July 2010. Citation: Quinlivan R, Martinuzzi A, Schoser B. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V). Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD003458. DOI: 10.1002/14651858.CD003458.pub4. Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ABSTRACT Background McArdle disease (Glycogen Storage Disease type V) is caused by an absence of muscle phosphorylase leading to exercise intolerance, myoglobinuria rhabdomyolysis and acute renal failure. Objectives To review systematically the evidence from randomized controlled trials of pharmacological or nutritional treatments for improving exercise performance and quality of life in McArdle disease. Search strategy We searched the Cochrane Neuromuscular Disease Group Specialised Register (17 May 2010), the Cochrane Central Register of Controlled Trials (Issue 2, 2010 in The Cochrane Library), MEDLINE (January 1966 to May 2010) and EMBASE (January 1980 to May 2010) using the search terms ’McArdle disease’, ’Glycogen Storage Disease type V’ and ’muscle phosphorylase deficiency’. Selection criteria We included randomized controlled trials (including cross-over studies) and quasi-randomised trials. Unblinded open trials and individual patient studies were included in the discussion. Interventions included any pharmacological agent or nutritional supplement. Primary outcome measures included any objective assessment of exercise endurance (for example aerobic capacity (VO2 ) max, walking speed, muscle force or power and fatigability). Secondary outcome measures included metabolic changes (such as reduced plasma creatine kinase and a reduction in the frequency of myoglobinuria), subjective measures (including quality of life scores and indices of disability) and serious adverse events. Data collection and analysis Three review authors checked the titles and abstracts identified by the search and reviewed the manuscripts. In the first review two authors (RQ and RB) independently assessed methodological quality of relevant studies and extracted data onto a specially designed form. In this update methodological quality of data was assessed by RQ and AM with comments from BS. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1 Main results We identified 31 studies,13 fulfilled the criteria for inclusion. Excluded trials are included in the Discussion. The largest treatment trial included 19 subjects. There was no benefit with: D-ribose, glucagon, verapamil, vitamin B6 , branched chain amino acids, dantrolene sodium, and high dose creatine. Minimal benefit was found with low dose creatine and ramipril only for patients with a polymorphism known as the D/D angiotensin converting enzyme (ACE) phenotype. A carbohydrate-rich diet resulted in better exercise performance compared with a protein-rich diet. Two studies of oral sucrose given at different times and in different amounts before exercise showed an improvement in exercise performance. Authors’ conclusions Although there was low quality evidence of improvement in some parameters with creatine, oral sucrose, ramipril and a carbohydrate rich diet, none was sufficiently strong to indicate significant clinical benefit. PLAIN LANGUAGE SUMMARY Pharmacological and nutritional treatment for McArdle disease McArdle Disease (also known as glycogen storage disease type V) is a disorder affecting muscle metabolism and is caused by the absence of an enzyme called muscle phosphorylase. This causes an inability to break down glycogen ’fuel’ stores. The condition leads to pain and fatigue with strenuous exercise. Sometimes severe muscle damage may develop and occasionally this results in acute reversible kidney failure. No benefit was found with the following treatments: D-ribose, glucagon, verapamil, vitamin B6 , oral branched chain amino acids, dantrolene sodium, high dose creatine and ramipril. Minimal benefit was found with low dose creatine and ramipril for patients who also have the D/D angiotensin converting enzyme (ACE) phenotype.Taking low dose creatine supplements has a minor benefit in improving exercise tolerance in a small number of people with the condition. Taking a sugary drink before planned strenuous exercise can improve performance but this treatment is not practical for day-to-day living. A diet rich in carbohydrate may be superior to a diet rich in protein but this evidence is based upon only a small number of participants. BACKGROUND McArdle disease (glycogen storage disease type V) is a disorder of muscle metabolism caused by the absence of the glycolytic enzyme, muscle phosphorylase. The first patient, described by Brian McArdle (McArdle 1951), presented with exercise induced myalgia and failed to produce a rise in blood lactate during ischaemic forearm exercise. In 1959 muscle phosphorylase was discovered and subsequently its deficiency confirmed in McArdle disease (Mommaerts 1959; Schmidt 1959). There is no detectable muscle glycogen phosphorylase activity in the majority of affected individuals. However in a small number, the levels of this enzyme are reduced (20% to 30% of normal values) but not absent (Beynon 1995). The inheritance of McArdle disease is autosomal recessive and heterozygotes are usually asymptomatic. The muscle phosphorylase gene is located at 11q13 and spans 20 exons (Bartram 1993). The most common mutation in Northern European and North American people is the nonsense mutation at R50X (previously referred to as R49X) (Kubisch 1998). Many different mutations in the gene have been identified (Andreu 2007). The preferred method of diagnosis is by muscle histochemistry following muscle biopsy. The consequence of muscle phosphorylase deficiency is the inability to mobilise muscle glycogen stores during anaerobic metabolism. To exacerbate the situation in McArdle disease, oxidative phosphorylation is also impaired because of an abnormally low substrate flux through the tricarboxylic acid cycle. This is most likely the result of virtual absence of pyruvate from glycolysis. This reduces the rate of acetyl-Co enzyme A formation, which in turn affects the tricarboxylic acid cycle. Acetyl-Co enzyme A can be generated from the breakdown of fatty acids, but without training, most individuals will have limited capacity for fatty acid oxidation during exercise (De Stefano 1996; Ruff 1998). The effect of this decline in oxidative phosphorylation is a decrease in oxygen consumption in affected individuals to 35% to 40% of that seen in normal muscle. Two other physiological effects may exacerbate the symptoms. Firstly a reduction in the blood flow of contracting muscle may lead to partial ischaemia (Libonati 1998). Secondly, a Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2 disproportionate increase in heart rate and ventilation rate occurs in affected individuals compared with normal controls (Vissing 1998). Most people present in the second or third decade, although symptoms are often reported retrospectively from childhood. With advancing age, a small proportion of people develop fixed muscle weakness predominantly affecting the shoulder girdle. The main complaints are exercise induced myalgia and fatigue. With severe sustained exercise through pain, a muscle contracture will occur and myoglobinuria (excretion of myoglobin, a muscle protein, in the urine causing dark discolouration), with or without acute renal failure, may follow due to acute rhabdomyolysis (breakdown of the muscles). The majority of people learn to manage their condition using an exercise pattern which exploits a phenomenon known as a ’second wind’. In McArdle disease, pain occurs within a few minutes of initiating exercise. However, if at this stage the person rests until the pain subsides there will be a metabolic shift to fatty acid oxidation enabling exercise to continue. This shift in metabolism occurs more effectively in individuals whose muscles have been conditioned through undertaking regular aerobic exercise. The diagnosis is suspected by the history and the finding of a raised plasma creatine kinase activity. Patients will fail to produce lactate during an ischaemic exercise test, although this test is not specific for the disorder and could potentially cause acute muscle necrosis and compartment syndrome. The definitive diagnosis is made by muscle histochemistry and the finding of absent functional muscle phosphorylase. In some cases DNA analysis for the common mutations can give an unambiguous diagnosis. There is considerable heterogeneity in the severity of symptoms, even in individuals who possess the same genetic mutation. The exact reasons are unclear, but might include modifying genes such as the angiotensin converting enzyme gene (ACE) and alpha actinin 3 (ACTN3) (Gomez-Gallego 2007; Lucia 2007; Martinuzzi 2007), differences in lifestyle including diet, fitness and aerobic capability. A study of 99 Spanish participants found a significant gender effect with females presenting with a significantly more severe phenotype than males (Rubio 2007). Because of the block in glycolytic metabolism, muscle activity occurring after the first few minutes of exercise is highly dependent on alternative energy sources including amino acids and free fatty acids. Research strategies have focused on increasing the availability of these substrates through either supplementation or dietary modification. At least 80% of the total body pool of vitamin B6 (pyridoxine) is in skeletal muscle bound to phosphorylase, and in McArdle disease this large pool of vitamin B6 is deficient (Haller 1983). The active form of vitamin B6 is an important co-factor for a number of enzymes involved in amino acid metabolism. Thus the extra demands placed on alternative fuel sources in McArdle disease may make people more dependent on vitamin B6 . Dantrolene sodium is used as a muscle relaxant for spasticity and for the prevention and treat- ment of malignant hyperthermia. Dantrolene decreases calcium flux from the sarcoplasmic reticulum, impairing the initiation of the excitation-contraction coupling mechanisms. A positive effect of dantrolene sodium in reducing exertional myalgia was reported in a single McArdle patient (Bertorini 1982). Creatine supplementation may increase the availability of adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and has been shown to benefit the exercise capacity of healthy individuals undergoing resistance training (Vandenberghe 1997) and to increase strength in people with mitochondrial myopathies (Tarnopolsky 1997). In McArdle disease magnetic resonance spectroscopy studies during exercise have demonstrated a rapid depletion of phosphocreatine with exercise, so creatine supplementation therefore might be beneficial. Upregulation of oxidative metabolism through diet, drugs or exercise might potentially increase the availability of a second wind. Thus, for example, an intravenous infusion of glucose during exercise enables glycolysis which in turn up-regulates oxidative phosphorylation (Haller 2002). The efficiency of muscle adaptation to training has been shown to be due to polymorphic variants of ACE. Polymorphisms leading to insertions or deletions (I/D) can affect muscle performance after training. In particular, the I allele which is associated with reduced ACE activity shows improved performance after aerobic training. Carrying the I/D ACE polymorphism affects phenotypic severity in McArdle disease (Gomez-Gallego 2007; Martinuzzi 2003). The use of pharmacological agents which inhibit ACE might improve performance in McArdle disease. In most people with McArdle disease, the primary genetic abnormality is a missense mutation in the PYGM gene leading to a stop codon. Certain drugs, for example the aminoglycoside, may allow the potential to read through stop codons and thus may induce the synthesis of a full-length protein (Barton-Davis 1999). This potential therapeutic strategy may be exploited with new pharmacological compounds for McArdle disease. OBJECTIVES To systematically review the evidence from randomized controlled trials examining the efficacy of pharmacological or nutritional treatments in improving exercise performance and quality of life in McArdle disease. METHODS Criteria for considering studies for this review Types of studies Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 3 We included randomized controlled trials (including cross-over studies) and quasi-randomised trials. Proof of principle physiological studies, open trials and single case studies without participant blinding were included in the Discussion. Types of participants We included males and females, both adults and older children (aged eight years and above) with a confirmed diagnosis based upon muscle histochemistry and/or unambiguous DNA studies. Types of interventions to May 2010). See Appendix 1, Appendix 2 and Appendix 3 for strategies. Open trials, single case studies and anecdotal reports identified during the main search were identified for possible inclusion in the discussion. Two unpublished studies conducted by authors of this review have also been included in the Results and Discussion. Searching other resources We reviewed the bibliographies of the randomized trials identified, contacted the authors and known experts in the field and approached pharmaceutical companies to identify additional published or unpublished data. We considered any pharmacological agent or micronutrient or macronutrient supplementation. Data collection and analysis Types of outcome measures Selection of studies Primary outcomes The primary outcome measure was level of change, after three months from start of treatment in exercise endurance objectively assessed by, for example VO2 max (aerobic capacity), walking speed, muscle force or power and improvement in fatigability. Secondary outcomes Secondary outcome measures after three months of treatment included: 1. metabolic changes including reductions in serum plasma creatine kinase and frequency of myoglobinuria together with metabolic changes seen on 31phosphorus- magnetic resonance spectroscopy (31P-MRS); 2. subjective measures including quality of life scores and indices of disability; 3. serious adverse events as measured by mortality and morbidity including adverse drug reactions, weight changes, atypical progression of the disease and poor quality of life scores. Search methods for identification of studies Three review authors (RB, RQ and AM) checked titles and abstracts identified and each review author independently assessed the full text of all potentially relevant studies. Data extraction and management Each review author assessed the full text independently using preagreed data extraction forms. Assessment of risk of bias in included studies Two reviewers (RQ and AM) decided which trials fitted the inclusion criteria and graded methodological quality, including allocation concealment, observer blinding, participant blinding, explicit diagnostic criteria and explicit outcome criteria. We aimed to obtain any missing data from the authors if needed. Data synthesis We did not subdivide the patient cohort into any subcategories. If appropriate data were available from more than one trial with a given intervention, we planned to undertake meta-analysis using the Cochrane Review Manager (RevMan) software to combine risk ratios or difference in means as a mean difference with 95% confidence intervals to provide pooled estimates. Electronic searches We searched the Cochrane Neuromuscular Disease Group Specialised Register (17 May 2010) using the following search terms: ’McArdle disease’, ’Glycogen Storage Disease Type V’ or ’GSDV’ or ’Muscle Phosphorylase Deficiency’. We adapted this search strategy to search the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2010 in The Cochrane Library), MEDLINE (January 1966 to May 2010) and EMBASE (January 1980 RESULTS Description of studies Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 4 See: Characteristics of included studies; Characteristics of excluded studies. Thirty-one studies were assessed of which 13 were identified as suitable for inclusion in the review (see Characteristics of included studies). In this update one new trial of oral sucrose was identified (Andersen 2008b) and a previously unpublished study of carbohydrate rich diet by Vissing 2007 is now published (Andersen 2008). The 31 studies evaluated the following treatments which showed no benefit: high dose oral ribose, fat rich diet, glucagon, verapamil, vitamin B6 , high protein diet, branched-chain amino acid supplementation, dantrolene sodium, high dose creatine, intravenous gentamicin, ketogenic diet and intralipid infusion. Treatments which showed some benefit included: low dose creatine, intravenous glucose, oral sucrose, carbohydrate-rich diet and ramipril. Because of the paucity of high quality studies, we decided to include studies with a treatment duration of less than three months. The excluded studies were either proof of principle studies to determine the physiological effects of specific metabolic fuels, open studies or single patient studies with no observer or participant blinding (these are summarised in the table entitled Characteristics of excluded studies) and will be discussed further in the Discussion section of this review. Risk of bias in included studies The risk of bias assessment for included studies is summarised in the table Characteristics of included studies The majority of studies included only a small number of participants or even single cases. There were no studies using the same treatment to allow any formal meta-analysis to be undertaken, apart from two trials using branched-chain amino acids and two studies of oral sucrose but with such different regimens as to preclude meta-analysis. A ’Risk of bias’ table using the methodology described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008) has been included . We assessed risk of bias for these studies using the judgements ’Yes’ to indicate a low risk of bias, ’No’ a high risk of bias and ’Unclear’ an unknown risk of bias. A Risk of bias summary with review authors’ judgements about each risk of bias item for each included study is included, see Figure 1. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 5 Figure 1. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 6 Effects of interventions Steele 1996 studied five participants with McArdle disease (four men and one woman, age range 20 to 60 years) in a double-blind randomized cross-over controlled study of oral ribose solution (15 g D-ribose made up in 150 ml water taken four times a day for seven days). Baseline measurements were made on no treatment, treatment and placebo. A Borg score for ratings of perceived exertion was used (Borg 1982). Participants underwent a weekly incremental exercise treadmill test with respiratory gas analysis. All five participants completed the trial, although some developed symptoms of hypoglycaemia which included light-headedness and hunger. One participant developed increased bowel frequency after ribose. Many found the drink too sweet and unpleasant to taste, and this may have compromised concealment. The study failed to show any normalisation of metabolic parameters or improved activity, although there was some normalisation of the ventilatory response to exercise. Day 1985 undertook a single-blind controlled trial of glucagon in one woman with McArdle disease. The diagnosis was based upon forearm ischaemic exercise testing and muscle biopsy which demonstrated absent phosphorylase activity. Isometric grip strength was measured in the left hand using a rolled sphygmomanometer cuff inflated to 200 mmHg. The grip strength at maximum effort was recorded at 10 second intervals. The participant was asked to report when the forearm became fatigued or painful, at which point exercise was stopped. Various treatments were assessed and neither the participant nor the investigator was aware of the treatment received. Measurements were performed no more than twice a day with at least six hours between the tests. Three baseline measurements were performed, after subcutaneous injection of saline (placebo), two measurements after 2 mg of subcutaneous glucagon and five measurements after administration of 2 mg depot glucagon. The endurance curves for different treatment modalities were plotted. There was a trend towards improvement with glucagon but this was not statistically significant when compared with placebo. Lane 1986 undertook a double-blind placebo controlled crossover study of the effect of verapamil on muscle pain. Three participants with McArdle disease (diagnosed by muscle biopsy) were studied compared with eight participants with an exertional pain syndrome of unknown cause. Participants were randomly assigned to a placebo or treatment group. After six weeks, medication was stopped for two weeks and then the two groups crossed over following the same regimen for another six weeks. The participants were asked to keep a pain and activity diary, at the same time each week the participants undertook specific timed exercise that would normally produce pain and the maximum level of pain graded on a scale of 0 to 10 during or following this task was recorded. None of the McArdle participants kept satisfactory diaries, two more participants withdrew from the study because of severe headaches and so were not included in the analysis. No significant benefit was observed in any of the McArdle cases. Beynon 1998 (unpublished data) undertook a randomized double blind placebo controlled cross-over trial of vitamin B6 . Ten participants (eight male and two female) with biochemically and genetically proven McArdle disease were given either placebo or vitamin B6 in a once daily dose of 50 mg. Ethical approval was obtained and participant data were compared with age and sex matched controls. Sachets containing either treatment or placebo were made up by the hospital pharmacy department and posted to the participants, who were randomly assigned to one of two groups. There was a six week wash out phase between treatment or placebo, which was given for ten weeks. Erythrocyte aminotransferase (eAST) activity was measured to assess vitamin B6 status and participants underwent programmed stimulation electromyogram (PSEM) to assess force generation and fatigability under ischaemic conditions. The investigators were unaware of the phase in the trial for each participant (i.e. placebo or treatment). No significant difference was found between the treatment and placebo. Kushner 1990 studied three patients and three controls comparing the immediate and long-term effects of oral branched-chain amino acids (BCAAs). The authors did not specify their diagnostic criteria and the age and sex of the participants were not revealed but the controls were age, sex, height and weight matched. Prior to the two month period of dietary supplementation, the participants underwent assessment daily for three days either in the fasting state or after immediate administration of 100 g dextrose or 0.3 g/ kg BCAAs, respectively. Participants were then assessed prior to, and after one and two months of BCAA dietary supplementation. Two types of muscle function were measured: maximal concentric strength and muscle endurance (absolute work performed to fatigue). Urine 3-methylhistidine/creatine ratio was measured. The study failed to demonstrate any immediate or long-term benefit from oral branched-chain amino acid supplementation. MacLean 1998 performed a single-blind controlled trial of BCAAs (leucine, isoleucine and valine) compared with a control noncalorific drink. The six participants (three males and three females) were unaware of treatment or placebo, but the investigators were not blinded to treatment. The participants were exercised for 20 minutes on a cycle ergometer at maximal intensity without experiencing pain or exhaustion. Work intensity converted to Watts and heart rate were measured. Levels of branched chain amino acids were measured in the bloodstream to assess for compliance. Despite increased availability of branched chain amino acids in the bloodstream, exercise capacity was lower in five of the six participants. The authors concluded that functional activity was worse with high dose branched-chain amino acids compared with fasting conditions. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 7 Poels 1990 studied the effect of dantrolene sodium on the second wind phenomenon. Five participants (two women and three men aged 21 to 41 years), in whom muscle phosphorylase protein was shown to be absent on sodium dodecyl sulphate-gel electrophoresis, were included in a randomized double-blind placebo controlled cross-over trial. Dantrolene was built up over three days to 150 mg, given in three divided doses of 50 mg. Treatment was given for six weeks with a four week washout period, followed by cross-over to either placebo or treatment. Dose dependent sideeffects were noted which included tiredness, somnolence, dizziness and muscle weakness resulting in four of the five participants reducing the dose. At the end of both treatment phases participants were tested on a bicycle ergometer at 30% VO2 max during two hours and after a 12 hour fast. Surface EMG was recorded during exercise. Participants were asked to use the Borg scale to rate their maximum perceived effort. Statistical analysis showed no significant symptomatic benefit with dantrolene. Vorgerd 2000 undertook a randomized double-blind placebo controlled cross-over study of creatine supplementation in nine enzymatically and genetically proven McArdle disease participants (six men and three women). Placebo was compared with creatine, initially at 150 mg/kg/day for five days followed by 60 mg/kg/day taken in three divided doses with meals. Each phase lasted five weeks followed by a four week washout period and then cross-over. Participants were asked to keep a symptom record of exercise intolerance using a fatigue severity scale devised by the authors. On the final day of treatment, clinical measures and laboratory tests were performed including 31-phosphorous magnetic resonance spectroscopy (31P-MRS), two sets of three minute static plantar flexion exercise under natural perfusion and ischaemic conditions (arterial occlusion). A substantial rise in plasma creatine was noted and the treatment was well tolerated. Five of the nine participants noted some subjective improvement when taking creatine compared with placebo, an increased tolerance of workload and depletion of phosphocreatine which increased significantly during ischaemic exercise as seen on 31P-MRS was demonstrated, although an overall increase in muscle phosphocreatine was not seen. A subsequent study undertaken by the same group (Vorgerd 2002) compared 60 mg/kg creatine with 150 mg/kg creatine given daily. Nineteen participants were studied in a double-blind placebo controlled trial. The outcome measures were the same as those used for the lower dose creatine trial. Treatment with high dose creatine significantly worsened the clinical symptoms of exercise-induced myalgia, the authors suggested that one possible explanation for this is that an insufficient adaptation to improved electromechanical efficacy leads to overuse of the muscle contractility in exercise and thus a worsening of symptoms. However no changes were seen on phosphorous 31P-MRS. Vissing 2003 undertook a single-blind randomized cross-over study of oral sucrose (75 g in a drink) compared with placebo (a drink with artificial sweetener) taken 30 to 40 minutes before fixed intensity exercise on a cycle ergometer for 15 minutes. Twelve par- ticipants (seven men and five women) aged 22 to 57 years, known to have McArdle disease (confirmed by muscle biopsy) were assessed on three consecutive days, one subject was taking an oral hypoglycaemic agent for type 2 diabetes. Subjects were studied following an overnight fast, the first day was used to define work protocols on a cycle ergometer for 15 minutes, ratings of perceived exertion (RPE) were recorded at one minute intervals, heart rate and workload were assessed. Blood samples were taken to measure glucose, lactate, pyruvate, ammonia, insulin, and free fatty acids. For the study 30 to 40 minutes before exercise, the participants received in random order 660 ml caffeine-free drink containing either artificial sweetener or sucrose 75 g. The method of randomization was not given and it is not clear whether the two drinks had identical taste. Only pooled subject data were given for all parameters. The mean plasma glucose rose significantly by 36 mg/dl compared with placebo and there was marked hyperinsulinaemia. The mean maximum heart rate was 156 (+/- 5) beats per minute following placebo but after sucrose the mean heart rate in the seventh minute of exercise was 34 (+/- 3) beats per minute lower than placebo and the rating of perceived exertion dropped when sucrose was ingested compared with placebo (P < 0.001) although the actual data were not given. The authors concluded that oral ingestion of sucrose can markedly improve exercise tolerance in McArdle disease. In the opinion of the authors, however, when used regularly, sucrose ingestion may result in weight gain. Furthermore it would be of no benefit for unprepared exercise where such pre-treatment could not be taken. Oral sucrose would be contraindicated in diabetics. Martinuzzi 2007 studied eight participants who were given 2.5 mg ramipril for 12 weeks in a double-blind randomized placebo controlled cross-over trial with a one month washout. The primary outcome measure was an objective assessment of performance using cycle ergometry. The secondary outcome measure was 31 phosphorous magnetic spectroscopy of the calf muscle during plantar flexion and subjective outcome measures including the World Health Organisation Disability Assessment Scale (WHODAS 11) and SF-36 (Short Form 36 Health Survey, a quality of life measure). SF-36 showed improvement in selected areas in both the treatment and placebo arms. No significant difference was found between the placebo and ramipril in objective exercise parameters, although the DAS-11 score improved in ramipril treated participants. The treatment was more effective in participants with the D/D ACE genotype, in whom it was associated with a slight but significant increase in peak VO2 although there was no improvement in any other exercise performance parameters. Andersen 2008b undertook study to look at the effect of oral sucrose given immediately before exercise. Six subjects (five men and one woman) were recruited with McArdle disease confirmed biochemically and with DNA studies. The participants were assessed on five separate mornings following an overnight fast. A baseline incremental exercise test using a bicycle ergometer was performed on day one to identify the participant’s maximal oxidative capacity Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 8 to establish the constant workload level to be used for the treatment studies. Participants were given either a caffeine free drink (660 ml) containing 75 g of sucrose or artificial sweetened placebo 40 minutes before exercise or a caffeine-free drink (330 ml) that contained sucrose or artificial sweetened placebo five minutes before exercise. Participants, but not assessors, were blinded. The various drinks were given in a random order, but the authors did not specify how randomization was performed. The participants cycled for 15 minutes at a constant workload of approximately 65% of their maximal oxidative capacity. Percieved exertion was assessed with the Borg RPE scale. Heart rate was monitored continuously and blood drawn periodically for glucose, insulin and lactate levels (the exact timing is not stated). Individual results were pooled, there was no difference for any variable between baseline cycling those following placebo and all participants demonstrated a second wind in the seventh minute of exercise. When 660 ml sucrose drink was given 40 minutes before exercise, improvements compared with placebo were reported with a decrease in RPP of 5.2 (P = 0.009) and a decrease in heart rate of 32 beats per minute (P = 0.02) (exact results were not published), plasma glucose levels decreased during exercise while lactate levels were higher than placebo but then decreased. When 330 ml sucrose drink versus placebo were given 5 minutes before exercise, improvements in the treatment group included an average drop in heart rate of 39 beats per minute ( P = 0.00004) and Borg RPP of 7.7 (P = 0.0008). Blood glucose levels increased and were higher in the second half of the exercise test. Insulin levels increased for both sucrose arms and were 300% higher than the 40 minute assessment. Andersen 2008 (previously reported as an unpublished study by Vissing 2007) compared carbohydrate-rich and protein-rich diets in a randomized cross-over study design with one week washout. Participants (6 male and one female) were assigned to either carbohydrate or protein diet according to the sequential order of subject recruitment. One subject was also known to have type 2 diabetes. Each participant was asked to follow a fixed diet with preset recipes for three days. Following a one week washout, participants switched to the other diet. The subjects were not observed while following the diet and were expected to prepare their own meals although they were given detailed instructions and asked to weigh and measure food ingredients and complete a form.The diet consisted of either 20% fat, 15% protein and 65% carbohydrate, or 55% protein, 30% carbohydrate and 15% fat. Outcome measures included response to cycle ergometry at constant workload at two- thirds of maximal exertion for 15 minutes followed by incremental workload until exhaustion. Maximum workload, heart rate and rating of perceived exertion were assessed together with blood biochemical measures of glucose, lactate and insulin. With the carbohydrate rich-diet there was a significant drop in heart rate and work effort P < 0.0005, although individual data were not given. The mean maximal oxygen uptake was 25% higher on the carbohydrate rich diet, 20.2 (+/- 1.2), compared with 16.1 (+/ -1.2) ml min−1 kg−1 ) than the protein rich diet (P < 0.0005). Results summary Although there have been a number of treatment trials for McArdle disease they have included only small numbers of participants (a maximum of 19 subjects in only one study (Vorgerd 2000)). Meta-analysis was not appropriate because there are virtually no replicated studies, irrespective of methodological quality and those studies that were replicated reported only pooled data from a small number of subjects expressed as a difference from baseline, which could not be analysed. There is a lack of evidence to show benefit from supplementation with branched chain amino acids, depot glucagon, dantrolene sodium, verapamil, vitamin B6 , high dose oral ribose or high dose creatine. Low dose creatine conferred a modest benefit on ischaemic exercise testing in five out of nine participants, although high dose creatine worsened symptoms. Oral ingestion of sucrose taken before exercise significantly improved exercise tolerance and had a greater benefit when given immediately before exercise. A diet rich in carbohydrate may be better than a protein-rich diet, but this evidence is based upon only small numbers of patients. Ramipril 2.5 mg orally daily showed some subjective improvement in participants with the D/D ACE polymorphism, which is thought to have a modulating effect on the condition, although there was no objective improvement in objective measures of exercise performance. DISCUSSION McArdle disease is a rare metabolic muscle disease and the paucity of subjects is the reason for the methodological difficulties seen in many of the studies. The largest randomized controlled trial reviewed included 19 participants and the remaining studies included no more than 12 participants. Eighteen further studies which were excluded from the review merit further description. Non-randomised studies (1) High protein diet Treatment with a high protein diet has been recommended in the past for people with McArdle disease, but there are no published randomized controlled trials to support its use. Two studies have looked at the effect of a high protein diet. Slonim 1985 studied a single affected male aged 50 years. The person suffered cramps on exertion and had significant upper limb muscle wasting and weakness and was confirmed to have McArdle disease following a muscle biopsy, which showed absent muscle phosphorylase on muscle histochemistry. The patient was initially studied during cycle ergometer exercise, serum lactate and alanine levels taken serially were compared with an age and sex matched control. The individual (but not control) was then studied on four separate occasions following a 10 hour fast after which either glucose or protein Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 9 (broiled beef ) were given orally, or saline or fructose were administered intravenously. The person was exercised carefully through a second wind phase and then exercised to exhaustion. The person exercised for a longer period of time following protein ingestion compared with the other nutritional interventions. A high protein diet and daily exercise (which included tennis) were recommended for three years. The participant was then re-tested following protein or glucose administration and after a mixed meal of his choice, comparison with a control for strength measurement was made after a mixed diet only. The authors reported anecdotal improvements in the person’s exercise ability and an improvement in strength in the upper limbs. There was no concealment of allocation and the person’s performance may have improved through practice. Furthermore, it is possible that the improvement in strength and endurance noted over the three year period was a consequence of the exercise programme which included one hour of aerobic exercise daily. Jensen 1990 studied the effect of a high protein diet for six weeks on a male participant with McArdle disease, confirmed by muscle biopsy. Bicycle ergometry was performed two hours after meals of the individual’s normal diet (15% protein, 42% fat and 43% carbohydrate) and after six weeks on an isocaloric high-protein diet (28% protein, 29% fat and 43% carbohydrate). Maximal muscle strength was measured by a stepwise increase in workload by 10W: two minutes work followed by 10 minutes rest. Endurance at submaximal muscle strength was measured after 15 minutes rest. Treadmill exercise combined with 31P-MRS was then studied two hours after a meal on the usual diet, following an intravenous glucose (20% solution) infusion, after an intravenous infusion of amino acids (0.3g/kg body weight/hr) and after six weeks of high protein diet. Six age matched normal controls were also examined with phosphorous-31 nuclear magnetic resonance (31-PNMR) to study adenosine triphosphate (ATP), phosphocreatine (Pcr) and inorganic phosphate (Pi). The controls did not receive any infusion. On his usual diet, the working capacity of the participant measured at treadmill exercise was approximately one half of that of the controls. ATP/(Pcr+Pi) and Pi/Pcr ratios were within the normal range at rest. During exercise there was a rapid decrease of Pcr and an equivalent rise in Pi, whereas ATP was unchanged at all levels of work load. During the intravenous glucose infusion, the expenditure of Pcr at each level of work load during hyperglycaemia was significantly less than during normoglycaemia. Following an increase of the daily protein intake from 15% to 28% on an isocaloric diet of unchanged carbohydrate content, the endurance at submaximal work load during bicycle ergometry was increased from five to eight minutes and the maximal capacity at graded bicycle exercise improved by 25%. Treadmill exercise performance improved by 40%. The 31P-spectrum showed decreased expenditure of Pcr at the maximum work intensities and the Pi/Pcr ratios improved from 3.1 at the usual diet to 1.5 at high protein diet. In comparison the Pi/Pcr ratios were 1.4 during glucose infusion and 4.4 during infusion of amino acids. Intravenous amino acid infusion at a rate of 0.3g/kg body wt/hr was not associated with any improvement of the phosphorous energy metabolism nor of the working capacity during treadmill exercise. The findings were an increase in performance and high energy kinetics following a high protein diet and glucose infusion, but not following administration of intravenous amino acids. There was, however, no concealment of allocation and statistical analysis was not appropriate because the study included only one participant. (2) High fat diet Pearson 1961 first described the second wind phenomenon and related this to delayed mobilisation and utilisation by the muscles of free fatty acids as a secondary energy source during muscle exercise. A beneficial action of a continuous infusion of emulsified fat in 4% glucose on the muscle performance of a participant was demonstrated. On the basis of this case report, Viskoper 1975 assessed the potential benefit of a high fat diet for three days in a single case study. The participant, an affected 21 year old male, was exercised on a bicycle ergometer at a workload of 60 kW for two and a half minutes. Later he was asked to maintain sustained abduction of the deltoid muscle to 90 degrees. Blood pressure was taken at one, two and five minutes, a blood sample was taken to measure free fatty acids, triglycerides and lactic acid, and EMG monitoring was conducted during eccentric exercise. The participant reported subjective feelings of increased fitness, but this could not be confirmed objectively by the researchers. In a second branch of the study isoprotenol was administered as a means of raising plasma free fatty acid levels, a dose of 10 mg three times a day was given for two weeks while the participant was on a normal diet. No beneficial effect was observed. Busch 2005 and Vorgerd 2007 described the effects of a ketogenic diet in one 55 year old male with McArdle disease by increasing the fat content of his diet by 80% with 14% protein for one year. His exercise tolerance was reported to be increased three to 10 fold. Maximum strength and activity also improved and CK levels reduced. Ketogenic diet did not alter 31P-MRS data during rest, work and recovery. Another observational study of ketogenic diet was set up to evaluate long-term effects of a ketogenic diet in one woman and three men with McArdle disease aged 41, 45, 48 and 52 years respectively (mean age 46 years), by increasing dietary fat content to 70% with 20% protein for 18 months. Serum ketone bodies, creatine kinase levels, maximum strength and 6 minute walking test were measured every eight weeks. After two months one man stopped the diet, the remaining subjects continued for 18 months. Creatine kinase levels fell by 40% but strength testing and the six minute walk test were not significantly improved. None of the subjects chose to continue with the diet (unpublished data, Schoser 2008). An unblinded observational study to evaluate the importance of lipids as an energy source during exercise was undertaken by Andersen 2009. Ten participants with McArdle disease (eight male Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 10 and two female) were required to cycle at a constant workload of 70% of their maximum oxygen consumption. On separate occasions in a random order they were given infusions of either normal saline, glucose, nicotinic acid (to block lipolysis) or 20% Intralipid (an intravenous lipid emulsion). Participants were required to cycle at a constant workload of 70% of their maximum oxygen consumption. Exercise capacity was determined by monitoring the heart rate response to exercise, which showed a significant increase with the intravenous lipid emulsion and nicotinic acid compared with normal saline and glucose. The authors concluded that although lipids are an important source of fuel during exercise, in people with McArdle disease there does not appear to be increased lipid metabolism during exercise. In another study of 11 participants with McArdle disease compared with 11 healthy controls, fatty acid oxidation during exercise was assessed using an intravenous solution of the radiotracer U-13 Cl Palmitate, and showed similar carbohydrate and fatty acid oxidation in both groups. However, during exercise performed on a cycle ergometer there was an increase in fatty acid oxidation in the McArdle patients compared with the control group during the second wind. However, following the second wind despite increased plasma levels of free fatty acids there was no further increase in fatty acid oxidation. The authors concluded that the key role of glucose is to facilitate fat oxidation and thus the block in glycogenolysis in McArdle disease may limit the capacity for fat oxidation (Orngreen 2009). Thus, when considering treatment aimed at enhancing fat use in McArdle disease, consideration should be given to adding interventions aimed at modifying the tricarboxylic acid pathway. (3) Glucagon administration There have been three studies to evaluate glucagon. The study by Day et al. (Day 1985) is included in this review and did not report any demonstrable effect with glucagon supplementation. Two earlier studies excluded from the review merit further discussion. Kono et al. (Kono 1984) gave glucagon to a single female participant aged 26 years. No placebo was used and there were no control subjects. Blood levels for creatine kinase, lactate dehydrogenase, glucose, free fatty acids and ammonia were measured. The participant was exercised for three minutes. The authors suggested that glucagon improved exercise tolerance. The participant was not assessed blindly and had also co-incidentally been taking coenzyme Q10 for one year which had resulted in a subjective improvement of her symptoms. Subcutaneous glucagon administration improved work tolerance on a bicycle ergometer. Normally the participant was exhausted after three minutes but with glucagon she exercised for 30 minutes with a second wind at three and ten minutes. An ischaemic lactate test undertaken with glucagon led to a rise in plasma lactate. There were no controls, and no concealment of allocation and no statistical parameters were used because this was a single case study. Mineo 1984 stud- ied two female participants with McArdle disease aged 26 and 29 years, and two male cases with Tarui’s disease, aged 44 and 20 years. (Tarui’s disease is a glycogen storage myopathy caused by a deficiency of the glycolytic enzyme phosphofructokinase). One participant with McArdle disease and one with Tarui’s were exercised on a bicycle ergometer with and without glucagon pre-treatment following an overnight fast. All four participants underwent a modified ischaemic exercise test and were given the following: oral glucose, glucagon and glucose combined with insulin. The authors found that the participant with McArdle disease achieved a second wind more efficiently with glucagon administration during cycle ergometer exercise. No benefit was seen in the case with Tarui’s disease. This study lacked concealment and statistical analysis. Further studies would be necessary to determine whether regular use of glucagon would benefit patients. However, any consideration of the use of glucagon as a form of possible therapy for McArdle disease should also be considered in context of its longterm side-effects, which include haemolytic anaemia. (4) Other interventions Non-randomised studies for other interventions have included vitamin B6 , oral ribose, intravenous glucose, creatine and gentamicin. Phoenix 1998 reported the effect of withdrawal of daily 50 mg vitamin B6 in a male participant with McArdle disease. The participant had been taking vitamin B6 as a supplement for two years. The effect of withdrawal of treatment was assessed. The participant was blind to receiving either vitamin B6 or placebo, which was allocated by the hospital pharmacy after a period of observation. The outcome was assessed using vitamin B6 status as assessed by eAST activity. Objective muscle function was evaluated by stimulation of the adductor pollicis muscle via the ulnar nerve at the wrist using programmed stimulation electromyography (PSEM) providing information on force and compound muscle action potential (CMAP) together with qualitative data on symptoms. Qualitative changes in feelings of reduced well being were noted off treatment and there was a rapid decline in vitamin B6 status. The PSEM studies showed a reduction in the participant’s ability to recover during the post ischaemic recovery phase during withdrawal of vitamin B6 although there was no clear effect of vitamin B6 on the CMAP. Vitamin B6 withdrawal did not affect the serum creatine kinase levels or frequency of myoglobinuria. Wagner 1991 assessed the effect of high dose oral ribose given to a 20 year old patient and six normal controls, which were not matched for age or sex. While the participant was pedaling a cycle ergometer, 3 g oral ribose was given every ten minutes. The study reported an increase in exercise capacity from 60 W to 100 W. Blood lactate levels were tested before and after exercise. The participant reported fewer cramps although there were no quantitative or qualitative assessments to substantiate this. Lewis 1985 showed that intravenous glucose is associated with a Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 11 partial normalisation of an excessive cardiac output in response to exercise together with improved exercise tolerance. They studied a single male with McArdle disease and two normal controls (one male and one female). The 31P-NMR of the forearm flexor muscles was assessed during exercise using a handgrip dynamometer (modified to work in the magnetic field) to record maximal handgrip. Repetitive exercise was performed two hours post prandially on a normal mixed diet and during an intravenous infusion of 60 ml of a 50% glucose infusion. Under control conditions the person with McArdle disease fatigued with an impending muscle contracture at two minutes and 10 seconds. From rest to fatigue the participant’s forearm muscle PCr declined precipitously and Pi increased markedly but ATP was only slightly reduced. Plasma glucose levels rose three times during the glucose infusion, the participant performed maximal handgrip exercise for more than seven minutes. During glucose infusion PCr fell and Pi increased to a much lesser extent than under control conditions. In the healthy controls forearm PCr tended to decline similarly and Pi tended to increase less in the healthy participants than the person with McArdle disease. Exercise in the control participants was no different with the glucose infusion. Haller 2002 studied the effect of intravenous glucose on the second wind. They studied nine participants (eight with complete phosphorylase deficiency and one with 3% of normal phosphorylase activity). Participants exercised on a cycle ergometer for about 40 minutes. Initial work capacity was determined in the first six to eight minutes, then workload was reduced for five to 10 minutes. The workload was again progressively increased to determine peak performance at 25 minutes. Immediately afterwards 50 ml of 50% glucose was infused over one to two minutes followed by a continuous infusion of 10% dextrose at a rate of 6 ml/min for the duration of exercise. Exercise was continued for 40 minutes. Participants were assessed three times over a 24 month period and the mean results presented. Heart rate was continuously monitored, gas exchange and cardiac output were measured at rest and during peak exercise within six to eight minutes. The glucose infusion resulted in a 20% increase in oxidative capacity. O’Reilly 2003 studied a single case on and off creatine at a dose of 25 g/day for five days. The author was also the subject and thus, there was no concealment, he was exercised to exhaustion in the second wind phase of exercise, achieving a work rate of 275 to 325 W. No benefit was noted with creatine supplementation. Schroers 2006 tested the short-term efficacy of gentamicin in four participants with McArdle disease who had stop mutations. These were given daily intravenous gentamicin sulphate 8 mg/kg/day each day for ten consecutive days in an open study. Plasma creatine kinase levels decreased but not significantly. Participants were evaluated with 31P-MRS but no difference was detected. Further studies on myoblasts demonstrated no increase in phosphorylase expression. Thus, short-term gentamicin treatment appeared to have no effect on performance in McArdle disease. It might be that the treatment was not given for long enough or the type of non-sense mutation was not amenable to the effects of the drug. The development of new compounds which induce read-through of stop codons, such as ataluren (PTC 124), and drugs that might up-regulate the brain phosphorylase isoform, such as valproic acid, could be promising. Initial studies on cell culture and animal models are required before large scale clinical trials can be contemplated. (5) Outcome measures A recurrent theme of therapeutic studies for McArdle disease is the restricted availability of patients. Future studies will need to be multi-centre and probably multinational. The limited evidence suggesting that females with McArdle disease may differ in phenotypic expression to males opens the question of considering a gender effect when planning future treatment trials. However, before such studies can be contemplated several key issues must be resolved. First is the need to specify rigorously defined methods for assessment of muscle performance and fatigue in McArdle disease. Whilst objective physiological tests are valuable in determining proof of principle, there is also a need for assessments that relate more to lifestyle and day-to-day demands on skeletal muscle, for example assessments of walking rather than cycling. The features of McArdle disease are fatigue, pain, speed of recovery and the onset of the second wind phenomenon. Future studies will need to be clear about which aspects of McArdle disease they wish to improve. There is at the moment too much emphasis on impairment (biochemical and physiological measurements) and not enough on disability (activities) and handicap (participation). Other challenges that have emerged from this review relate to the chemical composition of dietary supplements. For example a high protein diet does not seem to elicit the same effect as intravenous or oral amino acids. Once such issues have been adequately addressed, the path is clear for new studies to clarify the value of many of the treatments that have been addressed thus far in a limited fashion and to define modalities for new interventions. AUTHORS’ CONCLUSIONS Implications for practice Although there was low quality evidence of significant improvement in some parameters with low-dose creatine, oral sucrose, a carbohydrate-rich diet and ramipril, none was sufficient to indicate significant clinical benefit. Implications for research Further studies incorporating larger numbers of participants are needed to confirm the effectiveness of interventions including: low dose creatine, pre-exercise oral sucrose, dietary manipulation Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 12 (protein versus carbohydrate) and oral ramipril by defining patient groups according to ACE phenotype. More research is needed to determine optimum outcome measures, for example some assessments such as 31P-MRS, which is very sensitive at detecting metabolic changes, may be less effective in detecting clinically meaningful improvements, while assessments of daily activities such as walking may capture functional changes with greater sensitivity. Assessments of quality of life will also be useful in determining benefit although it is recognised that such scales have limitations. Because of the rarity of the disorder, multi-centre national and international collaboration will be required to produce high quality effective treatment trials. The development of standardised assessment protocols need to be developed once clear objectives have been agreed as to the phase and type of exercise to be assessed. This will determine the most effective means of measuring functional improvement in affected patients. ACKNOWLEDGEMENTS Rob Beynon was second author in the original review and first two updates. We thank the Muscular Dystrophy Campaign of Great Britain and the Association for Glycogen Storage Diseases (AGSD). We dedicate this review to Nicholas Owston, who sadly died in 2003, in acknowledgement of his untiring support through the AGSD. Editorial support from the Cochrane Neuromuscular Disease Group was funded by the TREAT NMD Network European Union Grant 036825. REFERENCES References to studies included in this review Andersen 2008 {published data only} Andersen ST, Vissing J. Carbohydrate- and protein-rich diets in McArdle disease: effects on exercise capacity. Journal of Neurology, Neurosurgery & Psychiatry 2008;79(12):1359–63. Andersen 2008b {published data only} Andersen ST, Haller RG, Vissing J. Effect of starting oral sucrose before exercise on work capacity in McArdle disease. Archives of Neurology 2008;65(6):786–9. Beynon 1998 {unpublished data only} Beynon RJ, Quinlivan RCM, Hopkins P, White L, Bartram C, Phoenix J. McArdle’s Disease: molecular genetics, clinical heterogeneity and a therapeutic trial. Muscle & Nerve. 1998; Vol. S30. Day 1985 {published data only} Day T J, Mastaglia F L. Depot-glucagon in the treatment of McArdle’s disease. Australian and New Zealand Journal of Medicine 1985;15(6):748–50. Kushner 1990 {published data only} Kushner RF, Berman SA. Are high-protein diets effective in McArdle’s Disease. Archives of Neurology 1990;47(4):383–4. Lane 1986 {published data only} Lane R J, Turnbull D, Welch J, Walton JL. A double-blind crossover study of verapamil in exertional muscle pain. Muscle & Nerve 1986;9(7):635–41. MacLean 1998 {published data only} MacLean D, Vissing J, Vissing S F, Haller RG. Oral branched chain amino acids do not improve exercise capacity in McArdle’s disease. Neurology 1998;51(5):1456–9. Martinuzzi 2007 {published data only} Martinuzzi A, Liava A, Trevisi E, Antoniazzi L, Frare M. Chronic therapy for McArdle disease: the randomized controlled trial with ACE inhibitor. Acta Myologica 2007;26(1):64–6. Poels 1990 {published data only} Poels PJ, Braakhekke JP, Joosten EM, Stegeman DF. Dantrolene sodium does influence the second wind phenomenon in McArdle’s disease. Electrophysioloical evidence during exercise in a doubleblind placebo-controlled, cross-over study in 5 patients. Journal of the Neurological Sciences 1990;100(1-2):108–12. Steele 1996 {published data only} Steele I C, Patterson V H, Nicholls D P. A double-blind, placebo controlled, crossover trial of D-ribose in McArdle’s disease. Journal of the Neurological Sciences 1996;136(1-2):174–7. Vissing 2003 {published data only} ∗ Vissing J, Haller RG. The effect of oral sucrose on exercise tolerance in patients with McArdle’s disease. New England Journal of Medicine 2003;349(26):2503–9. Vorgerd 2000 {published data only} Vorgerd M, Grehl T, Jager M, Muller K, Freitag G, Patzold T, et al.Creatine therapy in myophosphorylase deficiency (McArdle’s disease) A placebo controlled crossover trial. Archives of Neurology 2000;57(7):956–63. Vorgerd 2002 {published data only} Vorgerd M, Zange J, Kley R, Grehl T, Husing A, Jager M, et al.Effect of high-dose creatine therapy on symptoms of exercise intolerance in McArdle’s disease: double-blind, placebo-controlled crossover study. Archives of Neurology 2002;59(1):97–101. References to studies excluded from this review Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 13 Andersen 2009 {published data only} Andersen ST, Jeppesen TD, TaivassaloT, Sveen ML, Heinicke K, Haller RG, et al.Effect of changes in fat availability on exercise capacity in McArdle disease. Archives of Neurology 2009;66(6): 762–6. Busch 2005 {published data only} Busch V, Gempel K, Hack A, Muller K, Vorgerd M, Lochmuller H, et al.Treatment of glycogenosis type V with ketogenic diet. Annals of Neurology 2005;58(2):341. Vorgerd 2007 {published data only} ∗ Vorgerd M, Zange J. Treatment of glycogenosys type V (McArdle disease) with creatine and ketogenic diet with clinical scores and with 31P-MRS on working leg muscle. Acta Myologica 2007;26(2): 61–3. Haller 2002 {published data only} Haller RG, Vissing J. Spontaneous “second wind” and glucoseinduced “second wind” in McArdle disease. Archives of Neurology 2002;59(9):1395–402. Additional references Jensen 1990 {published data only} Jensen KE, Jacobson J, Thomsen C, Henriksen O. Improved energy kinetics following high protein diet in McArdle’s syndrome. A 31P magnetic resonance spectroscopy study. Acta Neurologica Scandinavica 1990;81(6):499–503. Kono 1984 {published data only} Kono N, Mineo I, Sumi S, Shimizu T, Kang J, Nonaka K, et al.Metabolic basis of improved exercise tolerance: Muscle phosphorylase deficiency after glucagon administration. Neurology 1984;34(11):1471–76. Lewis 1985 {published data only} Lewis SF, Haller RG, Cook JD, Nunnally RL. Muscle fatigue in McArdle’s disease studied by 31P-NMR: effect of glucose infusion. Journal of Applied Physiology 1985;59(6):1991–4. Mineo 1984 {published data only} Mineo I, Kono N, Shimizu T, Sumi S, Nonaka K, Tarui S. A comparative study on glucagon effect between McArdle disease and Tarui disease. Muscle & Nerve 1984;7(7):552–9. O’Reilly 2003 {published data only} O’Reilly DS, Carter R, Bell E, Hinnie J, Galloway PJ. Exercise to exhaustion in the second-wind phase of exercise in case of McArdle’s disease with and without creatine supplementation. Scottish Medical Journal 2003;48(2):46–8. 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Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. The Cochrane Collaboration, 2009. Available from www.cochrane-handbook.org. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 14 Kubisch 1998 Kubisch C, Wicklein EM, Jentsch TJ. Molecular diagnosis of McArdle’s disease: revised genomic structure of the phosphorylase gene and identification of a novel mutation. Human Mutation 1998;12:27–32. Libonati 1998 Libonati JR, Cox M, Incanno N, Melville SK, Musante FC, Glassberg HL, et al.Brief periods of occlusion and re-perfusion increase skeletal muscle force output in humans. Cardiologia 1998; 43(12):1355–60. Lucia 2007 Lucia A, Gomez-Gallego F, Santiago C, Perez M, Mate-Munoz JL, Chamorro-Vina C, et al.The 577X allele of the ACTN3 gene is associated with improved exercise capacity in women with McArdle’s disease. Neuromuscular Disorders 2007;17(8):603–10. Martinuzzi 2003 Martinuzzi A, Sartori E, Fanin M, Nascimbeni A, Valente L, Angelini C, et al.Phenotype modulators in myophosphorylase deficiency. Annals of Neurology 2003;53(4):497–502. McArdle 1951 McArdle B. Myopathy due to a defect in muscle glycogen breakdown. Clinical Science 1951;10:13–33. Mommaerts 1959 Mommaerts WFH, Illingworth B, Pearson CM, Guilorg RJ, Seraydarian K. A functional disorder of muscle associated with the absence of phosphorylase. Proceedings of the National Academy of Science USA 1959;3:18–22. Orngreen 2009 Orngreen MC, Jeppesen TD, Andersen ST, Taivassalo T, Hauerslev S, Priesler N, et al.Fat metabolism during exercise in patients with McArdle disease. Neurology 2009;72(8):718–24. Pearson 1961 Pearson CM, Rimor DG, Mommaerts WFHM. A metabolic myopathy due to absence of muscle phosphorylase. The American Journal of Medicine 1961;30:502–17. Rubio 2007 Rubio JC, Gomez-Gallego F, Santiago C, Garcia-Consuegra I, Perez M, Barriopedro MI, et al.Genotype modulators of clinical severity in McArdle disease. Neuroscience Letters 2007;422(3):217–22. Ruff 1998 Ruff RL. Why do patients with McArdle’s disease have decreased exercise capacity?. Neurology 1998;50(1):6–7. Schmidt 1959 Schmidt R, Mahler R. Chronic progressive myopathy with myoglobinuria: demonstration of a glycogenolytic defect in muscle. Journal of Clinical Investigation 1959;108:2044–58. Tarnopolsky 1997 Tarnopolsky MA, Roy BD, MacDonald JR. A randomised controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle & Nerve 1997;20:1502–9. Vandenberghe 1997 Vandenberghe K, Goris M, Van Hecke P, Van Leemputte M, Vangerven L, Hespel P. Long term creatine intake is beneficial to muscle performance during resistance training. Journal of Applied Physiology 1997;83(6):2055–63. Vissing 1998 Vissing J, Vissing SF, Maclean D, Saltin B, Quistorff B, Haller RJ. Sympathetic activation in exercise is not dependent on muscle acidosis. Direct evidence from studies in metabolic myopathies. Journal of Clinical Investigation 1998;108(8):1654–60. ∗ Indicates the major publication for the study Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 15 CHARACTERISTICS OF STUDIES Characteristics of included studies [ordered by study ID] Andersen 2008 Methods Carbohydrate rich diet versus protein-rich diet Participants 8 participants with McArdle disease Interventions Fixed menu plan with recipes for 3 days. Cross-over design Outcomes Incremental cycle test 2/3 max for 15 minutes then max to exhaustion. Notes Reduced heart rate and work load with the carbohydrate rich diet. Risk of bias Item Authors’ judgement Description Adequate sequence generation? No Participants were alternately allocated to carbohydrate or protein diet for the first arm or the study Allocation concealment? No Investigators enrolled participants according to the sequential order of inclusion Incomplete outcome data addressed? All outcomes Yes There were no drop outs or missing data Free of selective reporting? Yes Results were reported equally for both groups Free of other bias? No Participants were asked to follow recipes and weigh and record food on a form. There was no direct observation and food was not pre-prepared for the subjects Blinding? No Neither participant nor observer were blinded Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 16 Andersen 2008b Methods Sucrose immediately before exercise Participants 6 subjects (5 men and 1 woman) Interventions 660 ml caffeine free drink with 75 g sucrose or artificial sweetener 40 minutes before exercise or 330 ml caffeine free drink that contained 37 g sucrose 5 minutes before exercise Outcomes Cycle ergometry, heart rate, Borg RPP Notes Risk of bias Item Authors’ judgement Description Adequate sequence generation? Unclear The method of randomization was not given Allocation concealment? Unclear The method for allocation is not described Incomplete outcome data addressed? All outcomes Yes There were no dropouts or missing data Free of selective reporting? Unclear Individual data were not given, the only data are the pooled differences from baseline Free of other bias? Unclear The mean difference in heart rate was reported but the range of heart rate for each group was not reported Blinding? No Participants were blinded but observers were not blinded, it is not clear whether the placebo had an identical taste to the treatment Beynon 1998 Methods Randomised placebo controlled cross-over study. Participants 8 males and 2 females. Interventions 50 mg pyridoxine or placebo given for 10 weeks followed by 6 week washout period and then cross-over to the alternative treatment. Outcomes Erythrocyte AST activity to assess vitamin B6 status, PSEM to assess force generation and fatigability under ischaemic conditions. Notes No significant difference between treatment and placebo. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 17 Beynon 1998 (Continued) Risk of bias Item Authors’ judgement Description Adequate sequence generation? Yes Randomisation was performed using a computer generated program Allocation concealment? Yes Allocation was performed centrally by pharmacy staff Incomplete outcome data addressed? All outcomes No There were no drop-outs Free of selective reporting? Yes All of the results were reported Free of other bias? Yes No obvious other source of bias Blinding? Yes Both participants and observers were blinded Day 1985 Methods Single blind cross-over study. Participants A 42 year old affected female. Interventions 2 mg subcutaneous glucagon, 2 mg of depot glucagon and 1 ml normal saline subcutaneously. Outcomes Isometric grip strength under ischaemic conditions. Exercise endurance curves were plotted. Notes The participant subjectively felt better after depot glucagon but there was no statistically significant beneficial effect. Risk of bias Item Authors’ judgement Description Adequate sequence generation? Unclear The method of sequence generation is not described Allocation concealment? Unclear The method of allocation was not described Incomplete outcome data addressed? All outcomes Yes Data presented were complete Free of selective reporting? Yes Results from each intervention were equally reported Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 18 Day 1985 (Continued) Free of other bias? Yes No other source of bias identified Blinding? Yes Both participant and observers were blinded to intervention Kushner 1990 Methods Open controlled study. Participants 3 adults (age and sex not specified). 3 controls (age, sex, height and weight matched). Interventions Baseline assessments performed after fasting, 100 g of oral dextrose or 0.33 mg/kg BCAA. Participants were assessed after 1 and 2 months of 0.3 g/kg of dietary BCAAs as a supplement to their habitual diet. Outcomes Maximal concentric strength or torque at 60 cycles per minute and muscle endurance measured as absolute work performed to fatigue (60 or 90 cycles per minute with a 2 minute rest between sets). Notes No significant immediate or long-term improvement with BCAA supplements. Risk of bias Item Authors’ judgement Description Adequate sequence generation? No The method of sequence generation was not described Allocation concealment? No There was no allocation concealment Incomplete outcome data addressed? All outcomes Yes Data were complete for each intervention Free of selective reporting? Yes Data from each intervention were equally reported Free of other bias? Yes No other source of bias identified Blinding? No There was no participant or observer blinding Lane 1986 Methods Randomised double-blind placebo controlled cross-over study. Participants 3 adults with McArdle disease (2 male and 1 female aged 26, 44 and 24 years) and 8 people with an exertional muscle pain syndrome (6 males and 2 females aged 19 to 40 years). Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 19 Lane 1986 (Continued) Interventions 80 mg verapamil once daily for 3 days, twice daily for 4 days then three times daily for 5 weeks. After 6 weeks all participants stopped treatment for 2 weeks and then crossed over to the alternative treatment. Outcomes Pain diary which recorded the severity of muscle pain on a scale of 0 to 10, the amount of time spent reclining, sleeping, sitting and standing/ walking/ running for the same three hour period each day for 14 weeks, timed exercise test. Notes No effect. None of the McArdle cases kept satisfactory diaries. Risk of bias Item Authors’ judgement Description Adequate sequence generation? Unclear The method used for sequence generation was not described Allocation concealment? Unclear The method for allocation concealment was not described Incomplete outcome data addressed? All outcomes No None of the McArdle participants kept satisfactory diaries Free of selective reporting? No None of the McArdle patients kept adequate diaries Free of other bias? Yes No other source of bias identified Blinding? Yes Both participants and observers were blinded MacLean 1998 Methods Randomised single-blind placebo cross-over trial. Participants 6 participants, 3 male (50, 39 and 27 years) 3 female (42, 29 and 25 years). Interventions 77 mg/kg BCAA as a drink and a control 200 ml non- calorific drink. Outcomes Performance on cycle ergometer for 20 minutes at maximal intensity without experiencing pain or exhaustion. Notes No beneficial effect, exercise capacity was diminished after BCAA. Risk of bias Item Authors’ judgement Description Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 20 MacLean 1998 (Continued) Adequate sequence generation? Unclear The method used for sequence generation was not described Allocation concealment? Unclear The method of allocation concealment was not described Incomplete outcome data addressed? All outcomes Yes There were no drop outs or incomplete data Free of selective reporting? Yes There was equal reporting for placebo and treatment groups Free of other bias? Unclear It is not clear if the placebo and treatment had the same taste Blinding? No Only participants were blinded Martinuzzi 2007 Methods Randomised placebo controlled cross-over trial of ramipril. Participants 8 participants Interventions 2.5 mg ramipril daily for 12 weeks versus placebo for 12 weeks. Four week washout. Outcomes Cycle ergometry, maximal workload, maximum heart rate and maximum oxygen uptake.31P-MRS calf during plantar flexion, SF36 and WHO-DAS 11. Notes No difference in exercise capacity but improvement in DAS score with ramipril. Risk of bias Item Authors’ judgement Description Adequate sequence generation? Unclear The method of randomization was not given Allocation concealment? Unclear The method of allocation concealment was not stated Incomplete outcome data addressed? All outcomes Yes Data were reported equally for both groups Free of selective reporting? No Data are reported equally for both treatment and placebo groups Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 21 Martinuzzi 2007 (Continued) Free of other bias? Unclear Placebos were provided free of charge by the pharmaceutical company Blinding? Yes Both participants and observers were blinded Poels 1990 Methods Randomised double-blind placebo controlled cross-over trial. Participants 2 females (23 and 29 years) and 3 males (aged 21, 28 and 41 years). Interventions Placebo or dantrolene sodium 150 mg was given for 6 weeks, the dose was built up to 50 mg three times a day over 3 days. There was a 4 week washout period before crossover to the alternative treatment for a further 6 weeks. Outcomes Weekly subjective scores of improvement and serum CK. Performance on a cycle ergometer at 30% VO2 max after a 12 hour fast at the end of each treatment phase. Notes Four cases had to reduce the daily dose of dantrolene to 100 mg or 75 mg because of side effects. Subjective improvement in 1 case on treatment and 3 cases on placebo. No change in CK. levels. Positive EMG changes occurred during the treatment phase. Results were thus inconclusive. Risk of bias Item Authors’ judgement Description Adequate sequence generation? Unclear Method of randomization was not described Allocation concealment? Unclear Method of allocation was not described Incomplete outcome data addressed? All outcomes Yes There were no incomplete data Free of selective reporting? Yes Data from both treatment and placebo groups Free of other bias? No Side effects from treatment may have compromised blinding Blinding? Yes Particpants and observers were blinded Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 22 Steele 1996 Methods Randomised double-blind placebo controlled trial. Participants 4 males and 1 female age range 20 to 60 years. Interventions 15 g oral ribose four times a day for 7 days or placebo. Outcomes Muscle performance on treadmill with respiratory gas analysis. Notes No benefit, adverse effects noted, unpleasant taste, symptoms of hypoglycaemia and increased bowel frequency. Risk of bias Item Authors’ judgement Description Adequate sequence generation? Unclear The method of sequence generation was not described Allocation concealment? Yes The method of allocation concealment was not described Incomplete outcome data addressed? All outcomes Yes There did not appear to be any incomplete data Free of selective reporting? Yes Results were equally reported for treatment and placebo group Free of other bias? No Adverse effects of oral ribose may have compromised blinding Blinding? Yes Participants and observers were blinded Vissing 2003 Methods Randomised single-blind placebo controlled cross-over study Participants 7 males and 5 females aged 22 to 57 years. Interventions 75 g oral sucrose or placebo. Outcomes Heart rate, level of perceived exertion, blood glucose levels. Notes Significant reduction in perceived exertion and heart rate. Significant rise in blood glucose levels. Risk of bias Item Authors’ judgement Description Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 23 Vissing 2003 (Continued) Adequate sequence generation? No Treatment or placebo were given on consecutive days in a non-random order Allocation concealment? No There did not appear to be a method for allocation concealment Incomplete outcome data addressed? All outcomes Yes There were no dropouts Free of selective reporting? No Pooled peak heart rate data is given for placebo group but for the treatment group only the mean difference in heart rate is given Free of other bias? No It is not clear if the placebo and treatment had an identical taste Blinding? No Single blinded study where participants but not observers were blinded Vorgerd 2000 Methods Randomised double-blind placebo controlled cross-over trial. Participants 9 cases (6 females and three males aged 9 to 61 years). Interventions Placebo or creatine, loading dose for 5 days (150 mg/kg) then 60 mg /kg for 5 weeks then a four week washout period and cross-over to the other treatment. Outcomes Fatigue severity score, muscle P-31 MRS, 3 minute ischaemic exercise test. Notes Dizziness and headache in one participant during the treatment phase, no other adverse effects noted. Five participants reported improvement of muscle symptoms with treatment. Force-time intervals and depletion of creatine was significantly greater during ischaemic and aerobic exercise with creatine. The decrease of median frequency of surface EMG during contraction was significantly larger with creatine. Results were statistically significant. Risk of bias Item Authors’ judgement Description Adequate sequence generation? Unclear The method of randomization was not given Allocation concealment? Unclear The method for allocation concealment was not given Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 24 Vorgerd 2000 (Continued) Incomplete outcome data addressed? All outcomes Yes There were no dropouts or incomplete data Free of selective reporting? Yes Results were equally reported for both groups Free of other bias? Yes No other source of bias was identified Blinding? Yes Both participants and observers were blinded Vorgerd 2002 Methods Randomised double-blind placebo controlled trial. Participants 19 cases (8 females and 11 males aged 11 to 59 years). Interventions Creatine 150 mg/kg/day for 5 weeks versus placebo, washout period 4 weeks. Outcomes Subjective muscle symptoms, serum CK, creatine, P-31 MRS and surface EMG. Notes Increase in exercise induced pain, limitation of daily activity. Surface EMG revealed a smaller increase in amplitude over time with muscle contraction. No significant changes in muscle spectroscopy. Risk of bias Item Authors’ judgement Description Adequate sequence generation? Unclear The method used for sequence generation was unclear Allocation concealment? Unclear The method used for allocation concealment was unclear Incomplete outcome data addressed? All outcomes Yes There were no drop outs and complete data was reported Free of selective reporting? Yes There was equal reporting of results for both groups Free of other bias? Yes No other source of bias was identified Blinding? Yes Paticipants and observers were blinded BCCA: Branched-chain amino acid Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 25 CK: Creatine kinase EMG: Electromyography MRS: Magnetic resonance spectroscopy Characteristics of excluded studies [ordered by study ID] Study Reason for exclusion Andersen 2009 Non-blinded observational study, no concealment of allocation Busch 2005 Single case study Haller 2002 Three people with McArdle disease, no controls. No concealment of allocation. Jensen 1990 Single participant study with baseline controls data but controls did not receive intervention therapy. No concealment of allocation, no statistical analysis. Kono 1984 Single participant, no concealment of allocation. Participant concurrently self medicating with coenzyme Q10. Lewis 1985 Single participant with two normal controls. No concealment of allocation Mineo 1984 Two female participants with McArdle disease (GSDV) compared with two male cases with phosphofructokinase deficiency (GSDVII). No concealment of allocation. Only one GSDV participant and one GSD VII participant were assessed with bicycle ergometry. O’Reilly 2003 Single case study, no concealment of allocation. Phoenix 1998 Single case study, inadequate concealment of allocation. Schoser 2008 Longitudinal open study Schroers 2006 Single case study, no concealment of allocation. Slonim 1985 Single case study, no concealment of allocation. Viskoper 1975 Single participant, no concealment of allocation. Vorgerd 2007 Open design, no concealment of allocation. Wagner 1991 Single participant, no concealment of allocation. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 26 DATA AND ANALYSES This review has no analyses. APPENDICES Appendix 1. MEDLINE (OvidSP) Search Strategy 1 randomised controlled trial.pt. 2 controlled clinical trial.pt. 3 randomized.ab. 4 placebo.ab. 5 drug therapy.fs. 6 randomly.ab. 7 trial.ab. 8 groups.ab. 9 or/1-8 10 (animals not (animals and humans)).sh. 11 9 not 10 12 Glycogen Storage Disease Type V/ 13 (McArdle$ or (Glycogen Storage Disease adj5 Type V) or (Glycogen Storage Disease adj5 Type 5) or GSDV or (muscle phosphorylase adj5 deficiency)).tw. 14 12 or 13 15 11 and 14 Appendix 2. EMBASE (OvidSP) Search Strategy 1 crossover-procedure/ 2 double-blind procedure/ 3 randomised controlled trial/ 4 single-blind procedure/ 5 (random$ or factorial$ or crossover$ or cross over$ or cross-over$ or placebo$ or (doubl$ adj blind$) or (singl$ adj blind$) or assign$ or allocat$ or volunteer$).tw. 6 or/1-5 7 human/ 8 6 and 7 9 nonhuman/ or human/ 10 6 not 9 11 8 or 10 12 Glycogen Storage Disease Type 5/ 13 (McArdle$ or (Glycogen Storage Disease adj5 Type V) or (Glycogen Storage Disease adj5 Type 5) or GSDV or (muscle phosphorylase adj5 deficiency)).tw. 14 12 or 13 15 11 and 14 Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 27 Appendix 3. Cochrane Central Register of Controlled Trials search strategy #1“glycogen storage disease” NEAR/6 “type v” #2“glycogen storage disease” NEAR/6 “type 5” #3gsdv #4(muscle phosphorylase NEAR/6 deficiency) #5mcardle NEAR/2 disease #6“muscle phosphorylase” NEAR/6 deficiency #7(#1 OR #2 OR #3 OR #4 OR #5 OR #6) WHAT’S NEW Last assessed as up-to-date: 17 July 2010. Date Event Description 29 September 2010 New citation required but conclusions have not B Schoser joins review team as co-author. changed 17 June 2010 New search has been performed Searches were updated to May 2010. One new trial has been included and a previously unpublished study is now published. B Schoser replaced RJ Benyon as author. HISTORY Protocol first published: Issue 1, 2002 Review first published: Issue 3, 2004 Date Event Description 14 May 2008 Amended Converted to new review format. 20 February 2008 New citation required and conclusions have changed Since the last update of this review in 2004, there have been several new studies. An unpublished study comparing a carbohydrate rich diet with a protein rich diet demonstrated improved exercise performance with the carbohydrate rich diet (Vissing 2007). No benefit was observed with oral ramipril. Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 28 CONTRIBUTIONS OF AUTHORS RQ and RB were involved in the original review and agreed criteria for inclusion of studies and their methodological quality. RQ and MA were involved in assessing the two new studies included in the updated review. RQ completed the first and second updated drafts with agreement and approval from RB and MA. RQ completed this update with agreement and approval of AM and BS. DECLARATIONS OF INTEREST Two authors (RB and RQ) were involved in the conduct of a randomized cross-over placebo controlled trial of vitamin B6 , which did not demonstrate any overall benefit. One author (AM) was involved in the conduct of a randomized controlled trial of ramipril which did not demonstrate any significant benefit. One author (BS) was involved in an unblinded observational study of high fat diet which showed no benefit. SOURCES OF SUPPORT Internal sources • None, Not specified. External sources • None, Not specified. DIFFERENCES BETWEEN PROTOCOL AND REVIEW In this update of the review, the most recent trials were assessed for risk of bias according to the new Cochrane risk of bias assessment method (Higgins 2008). INDEX TERMS Medical Subject Headings (MeSH) ∗ Dietary Supplements; Creatine [administration & dosage]; Dietary Carbohydrates [administration & dosage]; Dietary Proteins [administration & dosage]; Glycogen Storage Disease Type V [drug therapy; ∗ therapy]; Randomized Controlled Trials as Topic MeSH check words Humans Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 29