Download Pharmacological and nutritional treatment for McArdle disease

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
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Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V) (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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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
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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)
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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.
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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.
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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
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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 &
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MacLean 1998 {published data only}
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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
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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}
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∗
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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.
Phoenix 1998 {published data only}
∗
Phoenix J, Hopkins P, Bartram C, Beynon R, Quinlivan RC,
Edwards RHT. Effect of vitamin B6 supplementation in McArdle’s
disease: a strategic case study. Neuromuscular Disorders 1998;8(34):210–2.
Schoser 2008 {unpublished data only}
Schoser B. Individual patient data (supplied 2008). Data on file.
Schroers 2006 {published data only}
Schroers A, Kley R, Stachon A, Horvath R, Lochmuller H, Gange
J, et al.Gentamicin treatment in McArdle disease: failure to correct
myophosphorylase deficiency. Neurology 2006;66(2):285–6.
Slonim 1985 {published data only}
Slonim A E, Goans PJ. Myopathy in McArdle’s syndrome:
improvement with a high protein diet. New England Journal of
Medicine 1985;312(6):355–9.
Viskoper 1975 {published data only}
Viskoper R, Wolf E, Chaco J, Katz R, Chowers I. McArdle’s
syndrome: the reaction to a fat rich diet. American Journal of
Medical Sciences 1975;269(2):217–21.
Wagner 1991 {published data only}
Wagner D R, Zollner N. McArdle’s disease: successful symptomatic
therapy by high dose oral administration of ribose. Klinische
Wochenschrift 1991;69(2):92.
Andreu 2007
Andreu A, Nogales-Gadea G, Cassandrini D, Arenas J, Bruno C.
McArdle disease: molecular genetic update. Acta Myologica 2007;
26(1):53–7.
Barton-Davis 1999
Barton-Davis ER, Cordier L, Shoturma DI, Leland SE, Sweeney
HL. Aminoglycodise antibiotics restore dystrophin function to
skeletal muscles of mdx mice. The Journal of Clinical Investigation
1999;104(4):375–81.
Bartram 1993
Bartram C, Edwards RHT, Clague J, Beynon R. McArdle’s disease:
a nonsense mutation in exon 1 of the muscle glycogen
phosphorylase gene explains some but not all cases. Human
Molecular Genetics 1993;2(8):1291–3.
Bertorini 1982
Bertorini T, Palmieri G, Bhattacharya S. Beneficial effects of
Dantrolene sodium in exercise-induced muscle pains: calcium
mediated?. Lancet 1982;1(8272):616–7.
Beynon 1995
Beynon R J, Bartram C, Hopkins P, Toesco V, Gibson H, Phoenix
J, et al.McArdle’s disease: molecular genetics and metabolic
consequences of the phenotype. Muscle & Nerve 1995;3:S18–22.
Borg 1982
Borg GA. Psychophysical bases of perceived exertion. Medicine and
Science in Sports and Exercise 1982;14(5):377–81.
De Stefano 1996
De Stefano N, Argov Z, Matthews PM, Karpati G, Arnold DL.
Impairment of muscle mitochondrial oxidative metabolism in
McArdle’s disease. Muscle & Nerve 1996;19(6):764–9.
Gomez-Gallego 2007
Gómez-Gallego F, Santiago C, Morán M, Perez M, Maté-Munoz
JL, Fernández Del Valle M, et al.The I allele of the ACE gene is
associated with improvement in exercise capacity in women with
McArdle disease. British Journal of Sports Medicine 2008;42:
134–40.
Haller 1983
Haller R G, Dempsey W B, Feit H, Cook J D, Knochel JP. Low
levels of muscle pyridoxine in McArdle’s syndrome. American
Journal of Medicine 1983;74(2):217–20.
Higgins 2008
Higgins JPT, Green S (editors). 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.
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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.
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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.
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