Neuromuscular Disorders
Volume 17, Issue 6 , Pages 494-498, June 2007

144th ENMC International Workshop: Outcome Measures in McArdle Disease, 29 September–1 November 2006, Naarden, The Netherlands

  • R. Quinlivan

      Affiliations

    • The Centre for Inherited Neuromuscular Disease, Robert Jones and Agnes Hunt NHS Trust, Gobowen, Oswestry, UK
    • Corresponding Author InformationCorresponding author.
    • ,
  • J. Vissing

      Affiliations

    • Neuromuscular Research Unit, Department of Neurology, and the Copenhagen Muscle Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

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1. Introduction 

Sixteen scientists and clinicians from across Europe and the USA met to discuss the use of outcome measures for future clinical trials with special reference to McArdle disease. Each participant presented the number of patients under their care, and facilities available for assessment. A cohort of 297 patients with McArdle disease was identified.

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2. Background 

The biochemical characteristics of McArdle disease were outlined (Beynon, UK). The disorder is caused by a congenital absence of the enzyme muscle phosphorylase due to autosomal recessive mutations in the myophosphorylase gene (PYGM). The complete lack of muscle phosphorylase leads to failure of glycolysis during anaerobic metabolism [1], [2]. Mutations in PYGM lead either to transcriptional failure at the mRNA level or an unstable protein due to missense mutations [3]. Nearly all patients have a zero protein phenotype, even though there may be molecular heterogeneity at the RNA level. The absence of functional myophosphorylase in nearly all patients with McArdle disease probably explains why no genotype/phenotype correlation has been described in the condition. However, one patient with a residual myophosphorylase activity of approximately 2%, and a much milder clinical phenotype has been described [4], indicating that phenotypic variability may occur in rare cases. Carriers of the condition have intermediate levels of myophosphorylase activity, but are asymptomatic [5]. The foetal isoform of phosphorylase in muscle is encoded by a different gene, and is expressed in regenerating muscle fibres. Expression of the foetal isoform on Western blot analysis is indistinguishable from the muscle form, however, mass spectrometry can distinguish between the two isoforms. It has been suggested that only 5–10% of functioning enzyme would be needed to alleviate symptoms in affected patients [6]. This probably explains why carriers of single PYGM mutations are asymptomatic. The prevalence of McArdle disease has been estimated to be 1:100,000, with a carrier frequency of 1:160 (Haller, USA) [7]. PYGM has 20 exons and 19 introns. More than 80 mutations have been identified to date, with some polymorphisms (Bruno, Italy). Table 1 shows the rate of hot spot mutations for different nationalities. Of the known mutations, 54 are nonsense mutations, 11 splicing, 12 deletions and 3 duplications. Silent polymorphisms appear to be involved in the regulation of splicing. Mutations in PYGM abolish phosphorylase activity, missense mutations affect contact dimmer pairs involved in the propagation of allosteric effects of regulatory protein [8]. Although there is no genotype/phenotype correlation there may be modifying effects of other genes especially insertion/deletions of the ACE gene (Martinuzzi, Italy) [9].

Table 1. Summary of most common mutations according to population (Bruno, Italy)
R50XG205sW798RSingle
British81%SporadicNR0
North American63%10%NK0
German58%Sporadic00
Spanish55%9%16.5%0
French56%NKNK0
Italian43%000
JapaneseNRNRNR55%

NR, none reported, NK, not known.

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3. Clinical phenotype 

The onset of the condition is typically in childhood, but the age of diagnosis is usually the second to fifth decade (Haller, USA). Premature fatigue is seen with isometric contraction due to either inhibition of the myosin ATPase or membrane inexcitability. Accumulation of potassium outside of the cell membrane leads to inactivation of ion channels. During a contracture there is inhibition of calcium ATPase. During the first 5–10min of exercise, muscle glycogen is crucial for delivering energy to contracting muscle. Consequently, there is a severe lack of substrate needed to fuel oxidative metabolism in patients with McArdle disease, and even trivial exercise intensities will elicit highly exaggerated heart rate responses in this time period. After 5–8min of exercise, the level of perceived exertion and the heart rate drop spontaneously with continued exercise due to increased availability of extramuscular fuels, such as hepatic glucose and fatty acids, which may partially compensate for the blocked muscle glycogenolysis. This significant improvement in exercise tolerance is called the second wind phenomenon, and is characteristic of McArdle disease. Exercise-induced symptoms include fatigue, tachycardia and breathlessness, a consequence of which is that some McArdle patients have been misdiagnosed with exercise-induced asthma.

The spontaneous second wind occurs in all patients after 5–8min of exercise (Haller, USA). Some patients deny ever experiencing a second wind, but when exercised in a laboratory, the second wind is a constant feature and is due to a glucose-mediated increase in oxidative phosphorylation. A low aerobic capacity leads to a low threshold for activation of anaerobic metabolism, which leads to increased susceptibility of fatigue, cramps and rhabdomyolysis. The severity of the condition relates to the level of aerobic fitness. Conditioning improves the circulatory system and increases the mitochondrial capacity to metabolise fuels. Thus conditioning is a major cause for variability of the phenotype.

Another factor that influences aerobic capacity and thus phenotype, is the availability of glucose and residual glycogenolysis. Patients with minimal residual myophosphorylase activity (1–2.5%) have a considerably higher oxidative capacity than patients with absent myophosphorylase (Haller, USA). There is no evidence to suggest that McArdle cases had any impairment of cardiac function due to lack of substrate [10].

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4. Atypical cases 

Atypical cases are reported in the literature, including late-onset and fatal infantile forms, and a form associated with congenital myopathy [11], [12], [13]. An atypical case of an 82-year-old male with late-onset severe weakness and wasting of his upper limbs from the eighth decade was described (Haller, USA). Eight cases with late-onset of symptoms were presented (Hilton-Jones, UK). One male was diagnosed at 48 years with a history of exercise intolerance and mild truncal weakness. A second male presented at 48 years with acute renal failure secondary to rhabdomyolysis. He had played squash every week for 20 years, but had always taken longer to warm up than his partner. He gave no history of muscle pain, on examination was found to have weakness of neck flexion. A third female patient presented with exercise-induced chest pain. She complained of aching thighs on exercise. Her exercise tolerance varied between a few metres and 400 metres. Four other cases presented over the age of 40 with exercise-induced fatigue and mild proximal muscle weakness. The distribution of weakness in six of these eight cases was more frequent for neck flexors than proximal shoulder and pelvic girdle.

French patients presenting over the age of 45 years were described (Laforêt, France). Out of 83 patients, 23 were over 45 years in age, 12/23 had no evidence of muscle weakness (ages 45–74 years) and 11/23 demonstrated muscle weakness (aged 46–80 years). Four patients had asymmetric weakness of the shoulder girdle, five had symmetrical proximal limb girdle weakness, two others had predominant axial involvement. One patient presented with exercise intolerance from 16 years of age, had a history of a second wind and myoglobinuria. From 46 years he developed scapular winging with severe pectoral, scapular and biceps atrophy. His muscle biopsy, in addition to absent phosphorylase activity, showed type 1 fibre predominance and ring fibres. DNA studies for FSH were negative. A second male patient hade scapular winging and severe upper limb weakness, he also required a pacemaker. DNA studies for LMNA were in progress. A third patient lost independent ambulation at the age of 64 years. He had brisk reflexes and severe shoulder atrophy. His muscle biopsy also showed ring fibres.

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5. Pharmacological and nutritional treatment trials 

The results of a Cochrane systematic review of pharmacological and nutritional treatment in McArdle disease found no evidence to suggest benefit from supplementation with oral d-ribose, glucagon, branched-chain amino acids, verapamil and dantrolene sodium (Quinlivan, UK). There have been few good quality randomised controlled trials due to the rarity of the disorder and paucity of available subjects. There is a need to develop standardised outcome measures, which represent daily living as well as physiological and biochemical parameters of function [14].

Eighty to ninety per cent of the body’s vitamin B6 (pyridoxal phosphate) is bound to phosphorylase (Beynon, UK). This pool of vitamin B6 is probably inaccessible metabolically [15]. However, it is possible that complete absence of phosphorylase has an effect on vitamin B6 metabolism. A single case study demonstrated apparent improvement with vitamin B6 supplementation [16]. A subsequent randomised placebo controlled crossover trial of vitamin B6 was undertaken. Ten McArdle patients and ten age- and sex-matched controls were given treatment or placebo for 12 weeks with a 6-week washout period between each arm. Force generation and fatigability were assessed using repetitive programmed stimulation electrophysiology (PSEM) of the abductor pollicis brevis muscle. No significant difference was found to exist between the treatment and control groups [14].

Oral glucose supplementation before exercise was studied in 12 patients who received either 75g sucrose or placebo in a drink 30–40min prior to exercise at a constant workload for 15min (Vissing, Denmark). Pre-exercise glucose was effective in reducing maximal heart rate and effort [17]. This might be a useful therapy prior to planned vigorous exercise, such as sexual intercourse. Regular use of glucose supplementation, however, is not recommended because of the potential for weight gain and glucose intolerance. In a further study, 50% of the amount of sucrose was given 5min before exercise and was shown to be equally effective (Vissing, unpublished data).

An unpublished crossover study of carbohydrate-rich versus protein-rich diets was described (Vissing, Denmark). Patients were asked to follow a fixed diet with pre-set recipes for three days. The diet consisted of either: 20% fat, 15% protein and 65% carbohydrate, or: 55% protein, 30% carbohydrate and 15% fat. Assessments were undertaken using cycle ergometry for 15min at two thirds of maximal exertion, followed by incremental work intensity to exhaustion. Exercise tolerance was significantly better when the patient was receiving a high carbohydrate diet.

Creatine is normally produced by the kidney. In muscle there is a sodium-dependent creatine transporter (Vorgerd, Germany). Phosphocreatine can donate a high-energy phosphate and rephosphorylate ADP to ATP. Oral creatine supplementation has been shown to improve muscle performance during resistive training [18]. In a randomised placebo controlled crossover trial, nine McArdle patients were given creatine 60mg/kg/day for 5 weeks. Outcome measures included a pain questionnaire, MR spectroscopy of the calf muscle with force-time integral aerobic low-dose exercise, and ischaemic low-dose exercise within the magnet. The results demonstrated an improvement in ischaemic exercise capacity, but not aerobic exercise with some improvement in symptoms [19]. A second study, using a higher dose of creatine (60mg/kg/day versus 150mg/kg/day) in 19 subjects, using the same outcome measures, lead to a worsening of exercise intolerance and an increase in impairment [20]. The same authors undertook an open trial of gentamicin in four subjects to explore the possibility of exon-skipping on myophosphorylase function, but the study showed no apparent benefit [21].

The use of a ketogenic diet in thirteen patients was described (Schoser, Germany). Ketogenic diets have been used for the management of severe intractable epilepsies with success. The side effects are weight loss, nausea, vomiting, constipation and vitamin deficiencies. In muscle, it down-regulates oxidative phosphorylation and promotes mitochondrial depletion. A single patient aged 55 years, managed on a diet of 80% fat and 14% protein (1760 calories), experienced improvement in exercise tolerance, and reduced creatine kinase was reported with no significant adverse effects [22]. A further four patients are currently being studied. Assessments include timed walking, cycling and stepping.

Insertions and deletions in the ACE gene are strongly associated with performance in resistance training. The D/D phenotype is associated with the worst performance (Martinuzzi, Italy). The ACE enzyme is found in skeletal muscle, and the D allele is associated with the poorest functioning McArdle patients [9]. Could an ACE inhibitor such as Ramipril improve performance? Eight patients were studied taking 2.5mg Ramipril for 8 weeks in a double-blind, randomised, controlled, crossover trial with a 1 month washout. The primary outcome measure was an objective assessment of performance. The secondary outcome measure was 31P MRS of the calf muscle during plantar flexion and subjective outcome measures including SF-36 and the WHO-DAS 11 (a disability assessment scale). No significant difference was found between the placebo and treatment, although the SF36 and DAS11 improved in both arms and was thought to be secondary to inclusion in a trial, i.e., placebo affect (Martinuzzi et al, unpublished data).

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6. Effect of training 

Aerobic training was studied in eight McArdle subjects (Haller, USA). Each was requested to train for 30–40min to 60–70% maximal heart rate four times each week. The creatine kinase varied from near normal to 30,000IU/l. The greatest improvement was seen in the first 5min of exercise due to an increase in oxidative capacity. Aerobic training at less than 70% maximum heart rate is safe. Regular aerobic exercise increases work capacity without symptoms of fatigue, cramping and pain [23].

The effects of endurance training in five patients and five controls using a short duration isometric test and long duration dynamic exercise were described (Portero, France). Patients underwent a 1-h cycle ergometer test, and 5–6min of exercise during phosphorous MR spectroscopy. No weakness was observed during the isometric fatigue test. The physiologic responses to exercise were the same for both the patient and control groups except the EMG results, which differed. During cycle ergometry to 30% max, the following were analysed: respiratory gas analysis, blood for glucose, lactate, CK, ammonia, pH, free fatty acids and EMG. Four patients and five controls underwent 8 weeks of aerobic training three times a week for 30–45min. The study showed that there was an improvement in oxidative capacity, an increase in glucose transport into the muscle cell, increased exercise tolerance and endurance, and a fall in CK with training in McArdle patients. The effect of training was the same for the McArdle patients as the controls (Portero et al., unpublished data).

Aerobic resistive strength testing, using a specially manufactured fly-wheel, was described (Zange, Germany). A pilot study of two affected patients, who underwent daily training for 12 weeks, demonstrated an improvement in strength without any significant adverse effects. There were no episodes of pain or cramping (Zange et al., unpublished data).

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7. Outcome measures 

The Bouchard questionnaire is a useful subjective assessment of energy expenditure. The questionnaire includes a 3-day activity record of physical activity, which is completed by the patient, and in which the patient scores physical activity every 15min (Laforêt, France). One weekend day is always included. The questionnaire has been validated in both adults and children and has been used to study 30 McArdle patients and 87 controls. In a study of McArdle patients, fatigue was perceived to be more important than pain in the patients, although the activity levels were similar for both the patient and control groups [24]. Fewer symptoms tended to be associated with a higher level of physical activity.

Cycle ergometry, using low maximal oxidative power 1/3–1/2 of normal, demonstrates a decrease in plasma lactate, second wind phenomenon and hyperkinetic circulatory response (Vissing, Denmark). To determine VO2max, patients should start cycling at 0W with 5–10W increments every other minute until exhaustion. Useful indicators that may be used as outcome measures are; heart rate, perceived exhaustion (Borg scale), workload, oxygen consumption, plasma lactate levels and cardiac output. Usually maximal VO2 is 14–28ml and maximal workload is 25–60W. A steady-state exercise test for 15min at 45% VO2max usually corresponds to a workload of 35W. Every patient has a second wind, and administering a glucose infusion will lead to a second, second wind. The second wind is pathognomonic for McArdle disease.

31P MRS can be used to measure intracellular pH and concentrations of the energy-rich compounds phosphocreatine and ATP (Vorgerd, Germany). The technique is time-consuming and expensive, and is therefore not an ideal tool to use in multi-centre treatment trials. Near infrared spectroscopy can monitor the oxygen extraction capacity of working muscle, but the method is not sufficiently validated to be used in treatment trials (Haller, USA). Furthermore, the technique has limitations, which include the condition of the muscles, the position of bridging veins and the amount of subcutaneous fat.

A 12-min walking assessment was described (Quinlivan, UK), using the Borg scale for rating of perceived pain and heart rate. A second wind is easily identified in all McArdle patients with this exercise method. The magnitude of the second wind and the maximum distance walked are useful measures of functional ability. The test can be performed in an outpatient clinic and requires no special equipment (Buckley et al., unpublished data).

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8. Conclusions 

At present there is no cure for McArdle disease. The clinical phenotype is fairly uniform, although a number of atypical cases were identified. Oral sucrose immediately prior to exercise and a high carbohydrate diet appear to be beneficial, however, the level of conditioning and frequency of aerobic training is probably the most effective mechanism for improving performance at present. All of the published treatment studies are based upon small numbers of subjects, and utilise laboratory-based physiological assessments. It seems likely that in the future genetic therapies may be available. For example, drugs which alter post-transcriptional read-through of a premature stop codon mutation may be of benefit for the approximately half of McArdle patients with the R50X mutation (Finkel, USA). Large-scale international multi-centre studies, which include measures of activity of daily living as well as functional, physiological and biochemical measures, will be required to assess their efficacy.

Based on this Workshop, a large multi-centre international natural history study will be undertaken. Full DNA sequencing of all patients will be obtained together with genotyping for ACE polymorphisms. Detailed assessments of muscle biopsy features and functional measures including assessments of muscle strength and endurance as well as subjective measures of functional ability and quality of life scales will be undertaken. It is hoped that this newly established clinical network will be in a position to consider large-scale clinical trials in the future.

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9. Participants list 


R. Beynon, Liverpool, UK

C. Bruno, Genoa, Italy

R. Finkel, Philadelphia, USA

R.G. Haller, Texas, USA

D. Hilton-Jones, Oxford, UK

P. Laforêt, Paris, France

M. Martin, Madrid, Spain

A. Martinuzzi, Conegliano, Italy

A. Mulas, Madrid, Spain

M. Orngreen, Copenhagen, Denmark

P. Portero, Paris, France

R. Quinlivan, Oswestry, UK

B. Schoser, Munich, Germany

J. Vissing, Copenhagen, Denmark

M. Vorgerd, Bochum, Germany

J. Zange, Koln, Germany

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Acknowledgements 

This Workshop was made possible thanks to the financial support of the European Neuromuscular Centre (ENMC) and ENMC main sponsors:

–Association Française contre les Myopathies (France)

–Deutsche Gesellschaft für Muskelkranke (Germany)

–Telethon Foundation (Italy)

–Muscular Dystrophy Campaign (UK)

–Muskelsvindfonden (Denmark)

–Prinses Beatrix Fonds (The Netherlands)

–Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland)

–Österreichische Muskelforschung (Austria)

–Vereniging Spierziekten Nederland (The Netherlands) and Associated member:

–Asociación Española contra las Enfermedades Musculares (ASEM)

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PII: S0960-8966(07)00082-X

doi:10.1016/j.nmd.2007.03.001

Neuromuscular Disorders
Volume 17, Issue 6 , Pages 494-498, June 2007

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