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doi: 10.1136/jnnp.2009.195040

online September 22, 20102010 81: 1182-1188 originally publishedJ Neurol Neurosurg Psychiatry

R Quinlivan, J Buckley, M James, et al.McArdle disease: a clinical review

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McArdle disease: a clinical review

R Quinlivan,1 J Buckley,1,2 M James,1 A Twist,1 S Ball,3 M Duno,4 J Vissing,4

C Bruno,5 D Cassandrini,5 M Roberts,6 J Winer,7 M Rose,8 C Sewry1

ABSTRACT

Methods The clinical phenotype of 45 geneticallyconfirmed McArdle patients is described.

Results In the majority of patients (84%), the onset ofsymptoms was from early childhood but diagnosis wasfrequently delayed until after 30 years of age. Not allpatients could recognise a second wind although it wasalways seen with exercise assessment. A history ofmyoglobinuria was not universal and episodes of acuterenal failure had occurred in a minority (11%). Thecondition does not appear to adversely affect pregnancyand childbirth. Clinical examination was normal in mostpatients, muscle hypertrophy was present in 24% andmild muscle wasting and weakness were seen only inpatients over 40 years of age and was limited to

shoulder girdle and axial muscles. The serum creatinekinase was elevated in all but one pregnant patient.Screening for the mutations pArg50X (R50X) andpGly205Ser (G205S) showed at least one mutated allelein 96% of Caucasian British patients, with an allelefrequency of 77% for pArg50X in this population. A 12min walking test to evaluate patients is described.

Conclusion The resultsdemonstrated a wide spectrumofseverity with therange of distance walked(195e1980 m);the mean distance walked was 512 m, suggestingsignificant functional impairment in most patients.

BACKGROUNDMcArdle disease (glycogen storage disease type V) isan inherited disorder of glycogen metabolismaffecting only skeletal muscle. Brian McArdledescribed a patient with exercise intolerance whofailed to produce lactate during ischaemic exercise.1

Subsequently, a deficiency of muscle glycogenphosphorylase was identified in patients withMcArdle disease.2 3 In most affected people there isno detectable glycogen phosphorylase activity.Traditionally, diagnosis is based on the inability ofthe patient to produce lactate during a forearm

exercise test, lack of muscle glycogen phosphorylaseactivity on muscle biopsy and, more recently, DNAstudies to look for variants in PYGM. Theischaemic lactate test has been replaced by a non-ischaemic forearm test which avoids the potentialrisk of compartment syndrome although there maybe a greater risk of false positive results.4 5 Afunctional cycle test has also been shown to bea useful screening assessment although the equip-ment required may not be widely available in anoutpatient setting.6

There are three isoenzymes of glycogen phos-phorylase, all of which have a high degree of amino

acid sequence homology. The muscle isoenzymeis encoded at 11q13 and is a prerequisite for

generation of ATP to fuel contracting muscle.7 It is

found in skeletal muscle and as a hybrid form in thebrain and cardiac muscle.8 There are also liver andbrain isoenzymes encoded by separate genes onchromosomes 14 and 20, respectively.9 The brainisoenzyme is present in fetal muscle and isexpressed in regenerating muscle fibres,10 11 and isalso expressed in smooth muscle. The histochem-ical method used to localise phosphorylase revealsthe activity of all three isoforms.

McArdle disease results from homozygous orcompound heterozygous mutations in themyophosphorylase gene (PYGM), on chromosome11q13. By December 2008, more than 100 muta-tions had been identified in the gene which spans20 exons and many of the mutations are populationspecific.12e14 The most common mutation inNorthern Europe and North American patients isa nonsense mutation at pArg50X (R50X) in exon 1(previously referred to as R49X).15 A secondfrequent mutation in the Northern American andSpanish populations is pGly205Ser (G205S).7 1 5 1 6

The diagnosis of McArdle disease is confirmed byDNA analysis and/or muscle biopsy with histo-chemistry and biochemical analysis.

In the resting state and during low intensityaerobic activity, skeletal muscle primarily utilisesfree fatty acids via oxidative phosphorylation for

energy. Absence of muscle glycogen phosphorylaseresults in the inability to mobilise muscle glycogenstores. This poses a problem to patients withMcArdle disease when there is a need for anaerobicmetabolism and a high glycolytic flux for oxidativecombustion. Typical symptoms include fatigue,muscle stiffness, myalgia and weakness which isinduced by exercise and relieved by rest.17 If exer-cise is continued despite these symptoms, painfulmuscle cramping and contracture followed bymyoglobinuria occurs. In severe cases, rhabdo-myolysis will lead to collapse and reversible acuterenal failure requiring dialysis. The second windphenomenon is universal in McArdle disease and

occurs due to a switch to alternative fuel substratesrequired for aerobic metabolism.6

In McArdle disease, a secondary impairment ofoxidative phosphorylation occurs due to a virtualabsence of pyruvate, which is normally generatedfrom glycolysis.18 Without physical training, mostindividuals will have limited capacity for fatty acidoxidation during exercise.1 9 2 0 The effect of thisdiminished oxidative phosphorylation is a reduc-tion in oxygen consumption to approximately 35%of normal and a disproportionate exercise inducedincrease in heart rate compared with normalcontrols.21

There have been no detailed epidemiologicalstudies of McArdle disease and there is little

1The Wolfson Centre for

Inherited NeuromuscularDisease, RJAH OrthopaedicNHS Trust, Oswestry, UK2The Centre for Exercise andNutrition Science, University ofChester, UK3The Princess Diana ChildrensHospital, Birmingham, UK4The Neuromuscular ResearchUnit, Departments of Neurologyand Clinical Genetics, NationalUniversity Hospital,Rigshospitalet, Copenhagen,Denmark5The Neuromuscular DiseasesUnit, Istituto Giannina Gaslini,Genova, Italy6Greater ManchesterNeurosciences Centre, HopeHospital, Salford, Manchester,UK7Department of Neurology,Queen Elizabeth Hospital,Edgbaston, Birmingham, UK8Department of Neurology,Kings College Hospital andKings College School ofMedicine, London, UK

Correspondence toDr R Quinlivan, The WolfsonCentre for InheritedNeuromuscular Disease, The

Robert Jones and Agnes HuntOrthopaedic and DistrictHospital NHS Trust, Oswestry,Shropshire, SY10 7AG, UK;[email protected]

Received 15 September 2009Revised 25 January 2010Accepted 28 January 2010Published Online First22 September 2010

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published data on the natural history of the condition althoughseveral authors have published data on the relative frequency ofspecific mutations occurring in patients in different Europeancountries.22 12 An incidence of 1:100000 has been reported forthe Dallas population (USA),23 and a small study of neonatalscreening for the pArg50X mutation in The Netherlandssuggested a frequency of 1:350 000.24 Among affected individ-uals there is marked heterogeneity in terms of severity, which

does not correlate with specific mutations.25 12 13

One possibleexplanation for variability in expression of the condition couldbe the coexistence of disease modifying genes such as theangiotensin converting enzyme gene phenotype, a actinin 3(ACTN3) and C34T muscle AMP deaminase (AMPD1).26e28

Differences in lifestyle, including dietary habit and fitness, arealso likely to play a role in variability.29

A specialist clinic for people with McArdle disease wasestablished at the Robert Jones and Agnes Hunt NHS HospitalTrust in 1998. In this study, we present the results ofa prospective clinical evaluation of 45 genetically confirmedBritish patients referred between July 1998 and December 2007.

A total of 55 patients previously diagnosed with McArdledisease were referred to the service BUT in 10 of these patientsthe clinical history was not considered typical for the conditionand further investigation (including forearm exercise test,muscle biopsy and PYGM studies) failed to confirm the diag-nosis. In nine of these patients, there had been a previouslyreported absence of muscle glycogen phosphorylase on musclehistochemistry and in one patient the diagnosis of McArdledisease had been made on the basis of an ischaemic forearmexercise test which gave a false positive result. Two of thesepatients were subsequently diagnosed with Becker musculardystrophy and one child was diagnosed with mini-core myop-athy. In the remaining seven patients the diagnosis was revisedto chronic fatigue syndrome/myalgic encephalopathy in accor-dance with the National Institute for Health and Clinical

Excellence diagnostic criteria for chronic fatigue syndrome/ME.30

METHODSThe 45 remaining patients were included in a prospective clinicalevaluation which included a detailed structured and stand-ardised history, clinical examination, functional assessment andinvestigations (serum creatine kinase (CK), plasma urate andmolecular genetic studies for mutations in PYGM, includingcDNA studies from whole muscle where appropriate). Struc-tured clinical history included the patients first memory ofexercise intolerance (where possible this was corroborated bya first degree relative), the age at which diagnosis was confirmedand the predominant symptom which caused the person to first

seek medical attention (although this might not necessarily haverelated to the consultation that led to diagnosis); specific ques-tions relating to the second wind phenomenon, myoglobinuriaand acute renal failure were also asked.

Results from previous investigations, including forearm exer-cise tests and muscle pathology, were not included in the datacollection; these investigations had been performed at manydifferent centres across the UK and at different times (some-times many years earlier) and as a consequence reliable andaccurate data might have been difficult to obtain but in allsubjects the diagnosis was confirmed by molecular analysis.

The resulting information was anonymised and recorded ontoa secure database and analysed separately by two individuals.

Approval for the clinical evaluation study was given by thehospitals audit committee. Approval was obtained from the

Shropshire ethics committee to develop a novel functional 12min exercise assessment, and informed written consent wasobtained from the participants.

We recognised that a pragmatic functional assessment wouldbe necessary to monitor individual patient progress on a routineoutpatient basis, hence the devising of a modified 12 minwalking test to assess functional ability. This was combinedwith a Borgs CR-10 scale31 to rate muscle sensations (fatigue,

tightness, discomfort, cramping and pain) on a 10 point scale.We chose the CR-10 scale for rating perceived muscle pain (RPP),rather than Borgs traditional scale of perceived exertion, for tworeasons: firstly, it has previously been used in conjunction witha timed walking assessment as a primary outcome measure fora clinical trial in McArdle disease,32 and secondly, the perceivedexertion scale was designed to measure the linear responses ofoverall aerobic body work whereas the CR-10 scale was designedto have congruence with the psychophysical phenomenon of thecurvilinear responses in perceptions to specific muscle sensationsduring exertion.34 35 Twenty of the 45 patients were recruited forthis study following informed written consent.

Each subject was asked to walk as far as they could in 12 minand to rate muscle sensation using the RPP scale. Subjects wereinstructed not to allow their RPP score to exceed level 4(moderate sensation). Heart rate was recorded via a wirelesschest strap transmitter (Polar, Kempele, Finland) and the totaldistance walked was recorded. Walking distance and thus speed,heart rate and RPP were recorded each minute. Differences inminimum and peak values of walking speed, heart rate andmuscle pain over the 12 min of the test were assessed using oneway analysis of variance.

RESULTSAge of onset and age at diagnosisThere was an equal preponderance of men (n22) and women(n23). Their ages ranged from 9 to 64 years. Table 1 summa-

rises the age of onset of symptoms and the age at which diag-nosis was made. The majority (n38, 84%) of patients recalledsymptoms before 10 years of age whereas only seven (15%)patients were diagnosed by 10 years of age. By contrast, 22patients (49%) were diagnosed after 30 years of age. Most indi-viduals reported that their symptoms in childhood had beenattributed to growing pains and not investigated further.

SymptomsThe features identified from patient histories are summarised intable 2. The most frequent symptom that precipitated 44/45 ofthe subjects to seek medical attention was painful musclecramping, with or without contracture, which involved anyskeletal muscle, including the proximal and distal limb, para-

spinal, chest and jaw muscles. One subject presented withrecurrent hospital admission due to episodes of unexplainedcollapse associated with myoglobinuria. He was subsequentlydiagnosed with juvenile myoclonic epilepsy, his myoglobinuriahaving been triggered by seizures. He denied any significant

Table 1 Age of onset and age of diagnosis

50years

Age of onset(n45)

38 (84%) 5 (11%) 2 (5%) 0

Age at diagnosis(n45)

7 (15 %) 8 (18%) 8 (18 %) 9 (20%) 8 (1 8%) 5 (11%)

84% reported onset of symptoms before 10 years of age; by comparison, 49% werediagnosed after 30 years.

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muscle symptoms other than a mild discomfort occurring withexercise. A faint trace of glycogen phosphorylase (rather thancomplete absence) was seen in his muscle histochemistry; therewere no regenerating muscle fibres. Genomic DNA studiesshowed him to have two PYGM sequence variants: pArg50Xmutation and a previously undescribed variation, c2430C>TcDNA studies from whole muscle suggested this novel variantwas likely to create an aberrant splice site.34 Cryptic splice

mutations can occasionally be leaky, allowing a minor fractionof correct splicing, which explains the milder phenotype. 34

Recognition by patients of a second wind, although typical forthe condition, was absent in 22% (n10), and severe contracturewith myoglobinuria had never occurred in 38% (n17). At leastone episode of acute renal failure necessitating haemodialysishad occurred in five patients (11%). Disabling central andperipheral fatigue with poor memory and concentration,resembling chronic fatigue syndrome, was relatively common,affecting 40% of all patients. A significant proportion of patients(31%) had been treated at some time for anxiety and/ordepression.

Two patients had come to medical attention followinga reported increase in frequency of muscle cramps after statintreatment had been prescribed for hypercholesterolaemia. Itremains unclear whether statin therapy actually worsenedsymptoms or merely led to the diagnosis being unmaskedbecause of routine CK monitoring. Five patients (11%) hadraised plasma urate levels and had been prescribed allopurinol forsymptomatic gout; one patient had a single episode of renalcalculi secondary to urate nephropathy. Affected adults (bothmen and women) reported muscle cramps, with or withoutmyoglobinuria, as a consequence of sexual intercourse. Mostpatients reported a sedentary lifestyle due to fear of developingrhabdomyolysis and acute renal failure.

Three patients had been treated with opiates prior to referral;two had become dependent on oral morphine and were unable

to withdraw treatment. All three reported severe exerciseintolerance due to incapacitating chronic pain, muscle crampsand myoglobinuria, despite continuous opioid treatment.

Physical examinationThe majority (71%, n32) of patients were overweight witha body mass index greater than 26. Facial weakness was not seenin any patient. Muscle hypertrophy was seen in 11 patients(24%) affecting all or some of the following muscle groups:deltoid, biceps, calves and thighs. Mild muscle wasting

predominantly involving the paraspinal, peri-scapular andproximal upper limb muscles was present in 15 patients (33%).Mild weakness (grade 4/5 Medical Research Council scale)involving axial and shoulder girdle muscles was seen in sevenpatients (16%), all of whom were over 40 years of age. Lowerlimb wasting and weakness was not a feature in the McArdlepatients. By contrast, quadriceps wasting and weakness wasseen in the two wrongly diagnosed patients who had Becker

muscular dystrophy.Progressive muscle wasting and limb girdle weakness was seen

in one patient with homozygous pArg50X mutations. Thepatient had marked calf hypertrophy and pes cavus, which wasnot seen in any other McArdle patient. In addition to completeabsence of muscle glycogen phosphorylase in most fibres, hismuscle biopsy showed atypical pathological features withseveral regenerating fibres with activity of the brain isoform ofphosphorylase and several rimmed vacuoles. Immunolabelling ofsarcolemmal proteins affected in various forms of musculardystrophy was normal (figure 1A, B shows typical histology forcomparison). The patient was thought to also be affected witha limb girdle muscular dystrophy. DNA studies for Xp21, FKRP,SMN, GNE and caveolin 3 showed no abnormality. Furthergenetic studies are pending.

InvestigationsSerum CK was raised in all but one female patient who was32 weeks pregnant at the time of testing. Mean serum CK was2471 iu/l (range 85e12405 iu/l, normal values

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minimum and peak values of walking speed, heart rate andmuscle pain over the 12 min of the test were assessed using oneway analysis of variance.

All 20 patients completed the assessment with no episodes ofsevere cramp or rhabdomyolysis (assessed by laboratorybiochemical analysis for CK and urine myoglobin concentra-tions). In the first 6 min of assessment, RPP ratings and heart

rate increased significantly from the resting value (p

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PregnancyData were based on reported experience from affected women,and suggests that McArdle disease does not significantlyincrease the risk of complications for pregnancy and delivery.Fourteen women had given birth to 21 children. Two womenreported worsening muscle cramps during pregnancy but therest reported feeling better than usual. There was one twindelivery and normal birth was achieved in 17/21. Two babieswere born by forceps delivery and two by emergency caesareansection, and one child was born following elective caesareansection because of a previous section. The rate of interventionaldelivery was 15%, which does not differ significantly fromhealthy women.36 One woman recalled mild myoglobinuria

following delivery of her third child but no specifi

c interventionwas required.

DISCUSSIONFollowing the development of a specialist clinic for McArdledisease, an unexpected finding was the relatively high frequencyof false diagnosis where 10 out of 55 patients previously diag-nosed did not have the condition. Two of the patients wronglydiagnosed with McArdle disease had Becker muscular dystrophy;both had presented with exertional cramps and myoglobinuria.Unlike the McArdle patients they both had quadriceps wastingand significant pelvic girdle weakness. Seven patients hadchronic fatigue syndrome, unlike the McArdle patients; none ofthese individuals complained of exercise related muscle crampsand all had a normal serum CK and ischaemic lactate test. Inthese patients the diagnosis of McArdle disease had been previ-ously made on the basis of muscle biopsy demonstrating absentphosphorylase activity. A repeat muscle biopsy, however, did notconfirm this finding.

The commonly used histochemical method is specific formuscle glycogen phosphorylase and in McArdle disease it fails tostain in mature skeletal muscle fibres. In regenerating musclefibres and smooth muscle fibres present in blood vessels it willstain positive because of the presence of the brain isoenzyme;this is a useful indicator that the method has worked. Themethod relies on activation and utilisation of the enzyme inreverse direction (glycogen synthesis), leading to the accumula-tion of glycogen, which is visible as iodine reactive material. Thecolour development is not stable in aqueous mountants and it isessential to include a control sample in parallel with the testsample and to observe the outcome as soon as possible toprevent a false diagnosis.7 If, however, the sections are dehy-drated and mounted in resins, the colour survives well and this

can avoid a false negative result.7 A false diagnosis of McArdledisease can also potentially occur in critically ill patients whohave secondary glycogen depletion; muscle histochemistry willappear negative for glycogen phosphorylase.37 On the otherhand, diagnosis can be missed if muscle biopsy is undertaken toosoon after massive rhabdomyolysis. Although the regeneratingfibres express the brain glycogen phosphorylase isoenzymestaining may appear weak. Under such circumstances it is wiseto delay muscle biopsy until at least 1 month after the patienthas fully recovered muscle function.

The diagnosis of McArdle disease can be confirmed bysequencing PYGM for mutations although this is timeconsuming and costly. Screening for the mutations pArg50X and

pGly205Ser before undertaking full gene sequencing is especiallyuseful for British Caucasian patients; it is cost effective and may

0.01

0.02

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210186420

Time (mins)

RPP/m

.min-1

03

04

05

06

07

08

09

210186420

WalkingSpeed(m.m

in-1)

Time (mins)

nim.m(deepsgniklaW1-)A

B

C

75

70

65

60

55

500 1 2 3 4 5 6 7 8 9 10 11 12

Heart rate (%maximum)

At each minute of a 12-min walking test

Figure 2 (A) Results of functional walking assessment (n20). Meanwalking speed (m/min) during a 12 min walk test. Error barsSE of themean. (B) Mean rating of pain (rating perceived muscle pain, RPP) towalking speed (m/min) ratio. Error barsSE of the mean. (C) Mean heartrate during the 12 min walk test, expressed as a percentage of peakheart rate corrected for age.

Figure 3 Individual patient results for maximal distance walked duringa 12 min walk test.


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prevent the need for a muscle biopsy and full gene sequencing. Inthis cohort, the allele frequency of the pArg50X mutation was77%. This confirms previous studies, which have shown thepArg50X mutation to be most prevalent in British and North

American patients.14 15

In this series, there was an equal preponderance of male andfemale patients, as would be expected for an autosomal recessivecondition. However, a previous retrospective review reported

a predominanceof affectedmales and concludedthat thisprobablyreflected a gender related reporting bias as males are more likely toundertake strenuous recreational and occupational activities.17

The onset of symptoms most commonly occurred in early child-hood but diagnosis was delayed until after 30 years of age in morethan half of the patients. The long delay from onset of symptomsto diagnosis despite patients seeking medical help suggests thatprimary care physicians are not familiar with the condition.

For many of the patients, memories of school years wereunfavourable, their symptoms having been attributed togrowing pains and not investigated further. In children, idio-pathic leg pains are common, they usually occur at night, are notexercise related and the serum CK is normal. By contrast, theserum CK is almost always raised in McArdle disease. Anypatient presenting with a history of muscle cramps affecting anyskeletal muscle during exercise should lead the doctor to suspecta metabolic myopathy. A history of painful cramps that occurwithin a few minutes of initiating exercise and which subsiderapidly with rest in conjunction with a raised serum CK ishighly suggestive of McArdle disease. If the individual continuesto exercise to the point of contracture, there will be a history ofpainful rigidity, which may persist for several hours; this willalmost always be accompanied by muscle swelling andmyoglobinuria. The history of a second wind should be specifi-cally looked for but may not always be recognised by patients.However, during exercise assessment the second wind isa universal finding.6A history of myoglobinuria is not universal

and its absence does not exclude the condition.In this series, significant muscle hypertrophy was present in

24% of patients, a more frequent finding than previouslyreported which was 10% in a cohort of 34 patients.13 Theaetiology of this finding is unclear. Mild muscle wastingaffecting the paraspinal muscles and shoulder girdle was rela-tively common. Muscle weakness, when present, was mild (notworse than MRC grade 4) and predominantly involved theshoulder girdle and axial muscles. Muscle weakness was not seenin any patient who was under 40 years of age. Significantshoulder girdle muscle atrophy and weakness has been previ-ously described in an elderly McArdle patient.38 The presence ofsignificant lower limb wasting and weakness was not a typicalfeature and alerted us to look carefully for an alternative diag-

nosis, which in this case was Becker muscular dystrophy.As with previous studies, we found no genotypeephenotype

correlation.1 2 1 3 In our research cohort, the 12 min walk testdemonstrated a wide range of variability (195e1980 m) but themean distance walked in 12 min was 512 m. Healthy sedentaryindividuals would be expected to walk more than 1200 m in12 min. McArdle patients who walk less than 500 m in 12 minare most likely to have significant impairment in performingactivities of daily living. The average walking speed of 41.7 m/min (2.5 km/h) in the research cohort represents an oxygenuptake of 8e10 ml/kg/min (2e3 metabolic equivalents)39; mostactivities of daily living range between 2 and 4 metabolicequivalents,40 which means that the McArdle patients achieving

less than 500 m were struggling to sustain what healthy indi-viduals would consider to be a very low exercise intensity.

People with McArdle disease are afraid to exercise for fear ofdeveloping rhabdomyolysis and acute renal failure but acuterenal failure was a relatively infrequent event and can be avoidedby pacing exercise intensity for the first few minutes of activity.Most patients adapt to their condition by adopting a sedentarylifestyle, the consequence of which will be de-conditioning andmay lead to exacerbation of fatigue and exercise intolerance.

Weight gain is common, with the majority of patients being

overweight or obese; this is likely to worsen symptoms byincreasing dependence on glycolytic metabolism during exercise.Psychological disturbance was a relatively common finding, andmay reflect a combination of living with limited exercise intol-erance and possibly diagnostic delay. Earlier diagnosis, improvedmanagement and a greater awareness of the condition couldpotentially improve quality of life.

In an open study of aerobic exercise training in people withMcArdle disease, Haller et al demonstrated a significantimprovement in work capacity and no serious untowardeffects.20 The authors concluded that the mechanism of actionwas likely to be an improvement in mitochondrial metabolismsecondary to an increased delivery of bloodborne mitochondrialfuels through improved blood flow.20 Thus aerobic exercise issafe for people with McArdle disease and should be recom-mended for all patients, regardless of age or severity.20 41 42

Advice should be given on how to avoid isometric musclecontraction and anaerobic exercise which are dangerous forpatients with McArdle disease and are likely to lead tocontracture and rhabdomyolysis.

In this series, three patients taking regular opiate medicationwere the most disabled and complained of incapacitatingchronic pain with frequent episodes of contracture andmyoglobinuria. There was no evidence to suggest symptomaticbenefit from opiatesdin fact, it is possible that this strong formof analgesia masks mild to moderate discomfort, the normalwarning sign to stop exercising before a cramp occurs, and thus

could potentially increase the frequency of episodes of contrac-ture and rhabdomyolysis.

The potential risk for adverse reactions to statins remainsuncertain. There are two published case reports of worseningcramps following statin treatment and one case report of acuterhabdomyolysis with Ezetimibe although the patient had alsoexercisedprior to the episode.43e45 In this series, twopatientswerediagnosed after a statin was prescribed. It remains unclear as towhether or notthe conditionwas made worseby statins or merelyunmasked in these patients.When considering statin treatment inpeople with McArdle disease, cautious introduction of treatmentwith close monitoring is advisable until further evidence becomesavailable on the effect of statins in the condition.

In this series there was an increased risk of symptomatic gout.

One patient also had a renal calculus, probably secondary toa urate nephropathy. This is probably due to a secondaryincrease in purine metabolism.46 The findings suggest thatplasma urate levels should be monitored in patients withMcArdle disease. Women can be reassured that a normal preg-nancy and delivery is possible.

There is no cure for McArdle disease, and as yet no specifictreatment can be recommended.29 Low dose creatine was shownto confer a small benefit in a small number of patients.47

Ingestion of sucrose prior to planned exercise improves perfor-mance48 but is not a useful treatment for routine daily living. Inone series, a diet rich in carbohydrate resulted in better exerciseperformance than a protein rich diet.49 Teaching patients

a strategy to achieve a second wind enables them to exercisesafely.

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A functional exercise assessment is necessary to monitor theeffectiveness of any future clinical intervention. Traditionally,exercise capacity in McArdle disease is assessed using cycleergometry which has been demonstrated to be reliable forphysiological and treatment studies.43 However, the lack ofavailability of sports equipment in many clinical settings makesthis test impractical for widespread routine outpatient use.Furthermore, walking is the most common and functional form

of physical activity and it seems sensible to have a simple testthat represents this activity. The assessment clearly demon-strated the presence of a second wind between 6 and 10 min, inkeeping with previous studies,24 where walking performanceclearly improved either by a reduction in discomfort for a givenwalking speed or that for any given heart rate, walking speedwas increased. This assessment additionally acts as an educa-tional tool because it enables patients to experience and clearlysee and understand the concept of a second wind. Finally,a record of the total distance walked in 12 min can be utilised asboth a functional status reference point and as a clinicaloutcome measure as an estimate of functional aerobic fitness.

Acknowledgements The authors would like to thank Mr Andrew Wakelin of the

Association for Glycogen Storage Disorders UK (AGSDUK) who gave feedback onthe manuscript, and Professors Roger Eston (University of Exeter) and Julius Sim(Keele University) who gave analytical advice. Financial support was given by theAGSD (UK) and the Muscular Dystrophy Campaign.

Funding AGSDUK, Muscular Dystrophy Campaign.

Competing interests None.

Patient consent Obtained.

Ethics approval The study was conducted with the approval of the Shropshire andStaffordshire Ethics Committee.

Provenance and peer review Not commissioned; externally peer reviewed.

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