Carbohydrate Ingestion before Exercise for Individuals with McArdle Disease: Survey Evidence of Implementation and Perception in Real-World Settings.

In individuals with McArdle disease (IWMD), the ingestion of carbohydrates before exercise has previously been shown in laboratory studies to significantly decrease the exercising symptoms of the condition and increase exercise tolerance during the early stages of exercise. As a result, carbohydrate ingestion pre-exercise is currently included in management guidelines, and often advised by medical professionals treating the condition. The aim of the current study was to determine whether positive lab-based results for the ingestion of carbohydrate before exercise in laboratory studies are being effectively translated into practice and produce perceptions of the same positive outcomes in real-world settings (RWS). An online survey method was used to collect responses from 108 IWMD. Data collected on the amount and type of carbohydrate consumed prior to exercise found that most surveyed participants (69.6%) who supplied qualitative data (n = 45) consumed less than the 37 g currently recommended in management guidelines. Survey data also revealed a large variation in the type and amount of carbohydrate ingested when IWMDs are applying carbohydrate ingestion before exercise in RWS. Consistent with these findings, only 17.5% of participants stated that they found carbohydrate ingestion before exercise relieved or minimised their MD symptoms. Results suggest that positive lab-based findings (increased exercise tolerance) of carbohydrate ingestion before exercise are not being effectively translated to RWS for many IWMD. There is a need for improved patient education of IWMD on the application of carbohydrate ingestion before exercise in RWS.

Long-Term Exercise Intervention in Patients with McArdle Disease: Clinical and Aerobic Fitness Benefits.

INTRODUCTION: The long-term effects of exercise in patients with McArdle disease-the paradigm of "exercise intolerance"-are unknown. This is an important question because the severity of the disease frequently increases with time. PURPOSE: This study aimed to study the effects of a long-term exercise intervention on clinical and fitness-related outcomes in McArdle patients. METHODS: Seventeen patients (exercise group: n = 10, 6 male, 38 ± 18 yr; control: n = 7, 4 male, 38 ± 18 yr) participated in a 2-yr unsupervised intervention including moderate-intensity aerobic (cycle-ergometer exercise for 1 h) and resistance (high load-low repetition circuit) training on 5 and 2-3 d·wk -1 , respectively. Patients were assessed at baseline and postintervention. Besides safety, outcomes included clinical severity (e.g., exercise intolerance features) on a 0-3 scale (primary outcome), and aerobic fitness, gross muscle efficiency, and body composition (total/regional fat, muscle, and bone mass; secondary outcomes). RESULTS: The exercise program was safe and resulted in a reduction of 1 point (-1.0; 95% confidence interval, -1.6 to -0.5; P = 0.025) in clinical severity versus the control group, with 60% of participants in the exercise group becoming virtually asymptomatic and with no functional limitation in daily life activities. Compared with controls, the intervention induced significant and large benefits (all P < 0.05) in the workload eliciting the ventilatory threshold (both in absolute (watts, +37%) and relative units (watts per kilogram of total body mass or of lower-limb muscle mass, +44%)), peak oxygen uptake (in milliliters per kilogram per minute, +28%), and peak workload (in absolute (+27%) and relative units (+33%)). However, no significant changes were found for muscle efficiency or for any measure of body composition. CONCLUSIONS: A 2-yr unsupervised intervention including aerobic and resistance exercise is safe and induces major benefits in the clinical course and aerobic fitness of patients with McArdle disease.

Rhabdomyolysis Episode in an Individual with McArdle's Disease after Low Aerobic Exercise.

McArdle's disease, known as blockage of muscle glycogen metabolism, is characterized by glycogen accumulation of chains in skeletal striated muscles. One of the typical symptoms of the disease is the feeling of intolerance to exercise. Severe muscle cram and contracture, which often cause stiffness, occur due to a lack of muscle energy substrate during the exercise. These factors can lead to muscle damage, myoglobinuria, and, in severe cases, renal failure and rhabdomyolysis. Rhabdomyolysis is a syndrome that presents injury and necrosis of muscle cells leading to the release of intracellular material to the circulatory system. The present study aimed to report rhabdomyolysis in an individual with McArdle's disease after exercise of walking with low intensity. Patient, aged 33 years, was treated in the emergency room of a hospital located in the State of Rio de Janeiro, Brazil. After performing a full lap on the block of home (~500 m in ~4 min 37 s), walking at a moderate speed (~6.5 km/h), the individual felt sick and was rescued, later being hospitalized. The examinations collected presented hematocrit (HCT) compatible with chronic disease anemia and myoglobinuria. The patient was discharged from the intensive care center on the 3rd day, after a 45% drop in creatine kinase. The patient described in the present study achieved full recovery. Attention to symptoms, early diagnosis, and immediate treatment made it possible to interrupt the development of complications caused by rhabdomyolysis, not allowing progression to acute renal failure.

[MCARDLE'S DISEASE AND PHYSICAL ACTIVITY - A MIXED BLESSING].

INTRODUCTION: McArdle disease (Glycogen storage disease type V) is a myopathy caused by an inherited deficit of muscle glycogen phosphorylase (PYGM). Since glycogen is an important fuel for muscular activity, people with McArdle's disease experience exercise intolerance. Dynamic or static vigorous exercise may lead to rhabdomyolysis, myoglobinuria and renal failure. Although exercise intolerance appears early in childhood, most people with McArdle's disease are diagnosed in the second or third decade of life. People with McArdle's disease tend to avoid exercise, despite its clear beneficial effects on health. As with many chronic diseases, medically supervised exercise with proper nutrition is possible, important, and beneficial to people with McArdle's disease.

Clinical Presentation and Management of Severe Acute Renal Failure in McArdle Disease.

McArdle disease, also known as glycogen storage disease type V, is an autosomal recessive disease due to the absence of myophosphorylase activity, leading to the complete disruption of glycogen breakdown in muscles. We present a rare case of a Caucasian male, aged 26 years, who developed rhabdomyolysis-induced acute renal failure and uremic encephalopathy. Neurological examination and histopathological studies supported the diagnosis of McArdle disease. The severity of his symptoms necessitated urgent hemodialysis, upon which the patient reported improvement in status. Acute renal failure in McArdle disease usually resolves with supportive treatment and maintenance of regular physical activity. Nevertheless, in more severe cases, intensive care with urgent hemodialysis may be needed. A multidisciplinary approach is necessary for the adequate management of similar cases.

Preclinical Research in McArdle Disease: A Review of Research Models and Therapeutic Strategies.

McArdle disease is an autosomal recessive disorder of muscle glycogen metabolism caused by pathogenic mutations in the PYGM gene, which encodes the skeletal muscle-specific isoform of glycogen phosphorylase. Clinical symptoms are mainly characterized by transient acute "crises" of early fatigue, myalgia and contractures, which can be accompanied by rhabdomyolysis. Owing to the difficulty of performing mechanistic studies in patients that often rely on invasive techniques, preclinical models have been used for decades, thereby contributing to gain insight into the pathophysiology and pathobiology of human diseases. In the present work, we describe the existing in vitro and in vivo preclinical models for McArdle disease and review the insights these models have provided. In addition, despite presenting some differences with the typical patient's phenotype, these models allow for a deep study of the different features of the disease while representing a necessary preclinical step to assess the efficacy and safety of possible treatments before they are tested in patients.

Exercise therapy for muscle and lower motor neuron diseases.

Muscle and lower motor neuron diseases share a common denominator of perturbed muscle function, most often related to wasting and weakness of muscles. This leads to a number of challenges, such as restricted mobility and respiratory difficulties. Currently there is no cure for these diseases. The purpose of this review is to present research that examines the effects of exercise in muscle and lower motor neuron diseases. Evidence indicates that moderate intensity aerobic- and strength exercise is advantageous for patients with muscle diseases, without causing harmful exercise-induced muscle damage. On the contrary, motor neuron diseases show a rather blunted response from exercise training. High-intensity training is a modality that seems safe and a promising exercise method, which may circumvent neural fatigue and provide effect to patients with motor neuron disease. Although we have come far in changing the view on exercise therapy in neuromuscular diseases to a positive one, much knowledge is still needed on what dose of time, intensity and duration should be implemented for different disease and how we should provide exercise therapy to very weak, non-ambulatory and wheelchair bound patients.

Pre- and peripartal management of a woman with McArdle disease: a case report.

McArdle disease or glycogen storage disease (GSD) type V is a rare autosomal recessive inherited disorder in skeletal muscle metabolism leading to exercise intolerance, muscle cramps and in some cases to rhabdomyolysis and acute renal failure due to elevated serum myoglobin levels. Albeit the uterine smooth muscle is not affected, pregnancy and delivery can be physically strenuous and may require specific anesthesiologic care. However, data on pregnancy progress and outcome and on special implications linked to anesthesia in women with McArdle's disease is scarce, thus posing a challenge to pre- and peripartal management. We report a case of a pregnant woman with Morbus McArdle who was monitored during her pregnancy and delivered a healthy male via cesarean section under spinal anesthesia. Pregnancy, delivery and recovery were uneventful. Our findings, combined with a literature review, lead to the conclusion that uncomplicated pregnancy and delivery can be expected.

Wave of renal impairment.

We present a case of a 51-year-old man who went to the emergency department after an almost-drowning episode, presenting with muscular weakness, myalgia and dark urine. Laboratory data showed a severe rhabdomyolysis (creatine kinase 497 510 U/L). Despite aggressive fluid therapy, an oliguric acute kidney injury was established with temporary need of haemodialysis. The patient had a longtime history of exercise intolerance and family history of a metabolic myopathy, namely a sister with McArdle's disease. The genetic test was positive. McArdle's disease is an autosomal recessive disorder caused by mutations in the muscle glycogen phosphorylase gene that encodes the myophosphorylase. The main symptom consists in exercise intolerance and the most severe complication is rhabdomyolysis with acute renal failure. Metabolic myopathies, such as McArdle's disease, should be considered in patients with acute renal failure due to unexplained severe rhabdomyolysis, especially if there are chronic complaints of exercise intolerance and positive family history.

Exercising with blocked muscle glycogenolysis: Adaptation in the McArdle mouse.

BACKGROUND: McArdle disease (glycogen storage disease type V) is an inborn error of skeletal muscle metabolism, which affects glycogen phosphorylase (myophosphorylase) activity leading to an inability to break down glycogen. Patients with McArdle disease are exercise intolerant, as muscle glycogen-derived glucose is unavailable during exercise. Metabolic adaptation to blocked muscle glycogenolysis occurs at rest in the McArdle mouse model, but only in highly glycolytic muscle. However, it is unknown what compensatory metabolic adaptations occur during exercise in McArdle disease. METHODS: In this study, 8-week old McArdle and wild-type mice were exercised on a treadmill until exhausted. Dissected muscles were compared with non-exercised, age-matched McArdle and wild-type mice for histology and activation and expression of proteins involved in glucose uptake and glycogenolysis. RESULTS: Investigation of expression and activation of proteins involved in glycolytic flux revealed that in glycolytic, but not oxidative muscle from exercised McArdle mice, the glycolytic flux had changed compared to that in wild-type mice. Specifically, exercise triggered in glycolytic muscle a differentiated activation of insulin receptor, 5' adenosine monophosphate-activated protein kinase, Akt and hexokinase II expression, while inhibiting glycogen synthase, suggesting that the need and adapted ability to take up blood glucose and use it for metabolism or glycogen storage is different among the investigated muscles. CONCLUSION: The main finding of the study is that McArdle mouse muscles appear to adapt to the energy crisis by increasing expression and activation of proteins involved in blood glucose metabolism in response to exercise in the same directional way across the investigated muscles.

Home-based aerobic exercise training improves skeletal muscle oxidative metabolism in patients with metabolic myopathies.

Aerobic training can be effective in patients with mitochondrial myopathies (MM) and McArdle's disease (McA). The aim of the study was to use noninvasive functional evaluation methods, specifically aimed at skeletal muscle oxidative metabolism, to evaluate the effects of an aerobic exercise training (cycle ergometer, 12 wk, 4 days/wk, ∼65-70% of maximal heart rate) in 6 MM and 7 McA. Oxygen uptake and skeletal muscle vastus lateralis fractional O2 extraction by near-infrared spectroscopy were assessed during incremental and low-intensity constant work rate (CWR) exercises before (BEFORE) and at the end (AFTER) of training. Peak O2 uptake increased significantly with training both in MM [14.7 ± 1.2 vs. 17.6 ± 1.4 ml·kg(-1)·min(-1) (mean ± SD)] and in McA (18.5 ± 1.8 ml·kg(-1)·min(-1) vs. 21.6 ± 1.9). Peak skeletal muscle fractional O2 extraction increased with training both in MM (22.0 ± 6.7 vs. 32.6 ± 5.9%) and in McA (18.5 ± 6.2 vs. 37.2 ± 7.2%). During low-intensity CWR in both MM and McA: V̇o2 kinetics became faster in AFTER, but only in the patients with slow V̇o2 kinetics in BEFORE; the transient overshoot in fractional O2 extraction kinetics disappeared. The level of habitual physical activity was not higher 3 mo after training (FOLLOW-UP vs. PRE). In MM and McA patients a home-based aerobic training program significantly attenuated the impairment of skeletal muscle oxidative metabolism and improved variables associated with exercise tolerance. Our findings indicate that in MM and McA patients near-infrared spectroscopy and V̇o2 kinetics can effectively detect the functional improvements obtained by training.

Exercise and Preexercise Nutrition as Treatment for McArdle Disease.

McArdle disease is due to an inborn defect in the muscle isoform of glycogen phosphorylase (or "myophosphorylase"), the enzyme that catalyzes the first step of glycogenolysis. This condition is still not fully understood, and although advances in research would help patients immeasurably, these would also enhance our understanding of exercise metabolism. It has been 10 yr since the first published report demonstrating the benefits of regular aerobic exercise for these patients. However, misconceptions remain and the value of exercise prescription for patients with McArdle disease is still overlooked. Here, we review the role of exercise in McArdle disease with the aim to better inform health-care professionals and thus better serve the interests of patients. Recommendations for regular exercise together with preexercise nutrition in children and adult patients are also provided along with examples of exercise practice and its benefits.

[25-year old patient with angina pectoris during religious fasting]. / 25-jähriger Patient mit pektanginösen Beschwerden während des muslimischen Fastenmonats.

UNLABELLED: HISTORY AND PRESENTATION AT ADMISSION: A 25-year-old male patient presented with acute left sided chest pain. The patient reported no physical exercise but daytime fasting (with neither food nor liquid intake) which he had started several days before. INVESTIGATIONS: ECG, echocardiography and chest X-ray were normal, but blood examination revealed elevated levels for creatine kinase (CK) and lactate dehydrogenase (LDH). Ischemic lactate ammonia test revealed no increase of lactate during exercise. Muscle biopsy confirmed suspected diagnosis of glycogen storage disease type V (McArdle's disease). TREATMENT AND COURSE: As causal treatments are unavailable for McArdle's disease, careful counselling regarding adequate exercise and regular, carbohydrate rich nutrition are mandatory to ameliorate symptoms. CONCLUSION: McArdle's disease represents a rare differential diagnosis of cardiac chest pain and somatoform myalgic complaints. When taking the patient's history, questions regarding the "Second wind"-phenomenon are helpful for initiating the adequate investigations early on.

The pathogenomics of McArdle disease--genes, enzymes, models, and therapeutic implications.

Numerous biomedical advances have been made since Carl and Gerty Cori discovered the enzyme phosphorylase in the 1940s and the Scottish physician Brian McArdle reported in 1951 a previously 'undescribed disorder characterized by a gross failure of the breakdown in muscle of glycogen'. Today we know that this disorder, commonly known as 'McArdle disease', is caused by inherited deficiency of the muscle isoform of glycogen phosphorylase (GP). Here we review the main aspects of the 'pathogenomics' of this disease including, among others: the spectrum of mutations in the gene (PYGM) encoding muscle GP; the interplay between the different tissue GP isoforms in cellular cultures and in patients; what can we learn from naturally occurring and recently laboratory-generated animal models of the disease; and potential therapies.

Pharmacological and nutritional treatment for McArdle disease (Glycogen Storage Disease type V).

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. This is an update of a review first published in 2004.Objectives To review systematically the evidence from randomised controlled trials (RCTs) of pharmacological or nutritional treatments for improving exercise performance and quality of life in McArdle disease.Search methods We searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE on 11 August 2014.Selection criteria We included RCTs (including cross-over studies) and quasi-RCTs. We included unblinded open trials and individual patient studies 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. Two review authors independently assessed the risk of bias of relevant studies, with comments from a third author. Two authors extracted data onto a specially designed form.Main results We identified 31 studies, and 13 fulfilled the criteria for inclusion. We described trials that were not eligible for the review in the Discussion. The included studies involved a total of 85 participants, but the number in each individual trial was small; the largest treatment trial included 19 participants and the smallest study included only one participant. There was no benefit with: D-ribose,glucagon, verapamil, vitamin B6, branched chain amino acids, dantrolene sodium, and high-dose creatine. Minimal subjective benefit was found with low dose creatine and ramipril only for patients with a polymorphism known as the D/Dangiotens in 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. Four studies reported adverse effects. Oral ribose caused diarrhoea and symptoms suggestive of hypoglycaemia including light-headedness and hunger. In one study, branched chain amino acids caused a deterioration of functional outcomes. Dantrolene was reported to cause a number of adverse effects including tiredness, somnolence, dizziness and muscle weakness. Low dose creatine (60 mg/kg/day) did not cause side-effects but high-dose creatine (150 mg/kg/day) worsened the symptoms of myalgia.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.

McArdle disease: a unique study model in sports medicine.

McArdle disease is arguably the paradigm of exercise intolerance in humans. This disorder is caused by inherited deficiency of myophosphorylase, the enzyme isoform that initiates glycogen breakdown in skeletal muscles. Because patients are unable to obtain energy from their muscle glycogen stores, this disease provides an interesting model of study for exercise physiologists, allowing insight to be gained into the understanding of glycogen-dependent muscle functions. Of special interest in the field of muscle physiology and sports medicine are also some specific (if not unique) characteristics of this disorder, such as the so-called 'second wind' phenomenon, the frequent exercise-induced rhabdomyolysis and myoglobinuria episodes suffered by patients (with muscle damage also occurring under basal conditions), or the early appearance of fatigue and contractures, among others. In this article we review the main pathophysiological features of this disorder leading to exercise intolerance as well as the currently available therapeutic possibilities. Patients have been traditionally advised by clinicians to refrain from exercise, yet sports medicine and careful exercise prescription are their best allies at present because no effective enzyme replacement therapy is expected to be available in the near future. As of today, although unable to restore myophosphorylase deficiency, the 'simple' use of exercise as therapy seems probably more promising and practical for patients than more 'complex' medical approaches.