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Myophosphorylase deficiency (glycogen storage disease V, McArdle disease)

Myophosphorylase deficiency (glycogen storage disease V, McArdle disease)
Author:
Sihoun Hahn, MD, PhD
Section Editor:
Helen V Firth, DM, FRCP, FMedSci
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Dec 2022. | This topic last updated: Jun 29, 2020.

INTRODUCTION — Myophosphorylase (muscle phosphorylase) deficiency (MIM #232600), historically known as McArdle disease, is the most common glycogen storage disease (GSD) affecting the muscle (figure 1) [1]. The GSDs are generally categorized by number according to the chronology of recognition of the responsible enzyme defect. As such, myophosphorylase deficiency is designated GSD V (table 1).

In myophosphorylase deficiency, glycogen is not properly broken down in muscle cells, interfering with their function. Patients typically present in adolescence or early adulthood with exercise intolerance, fatigue, myalgia, cramps, poor endurance, muscle swelling, and fixed weakness, but symptoms commonly are present in the first decade of life. Patients have resting elevations in creatine kinase (CK) and episodes of rhabdomyolysis. Genetic testing is the most reasonable and efficient method to confirm a diagnosis in patients with consistent clinical symptoms. A functional and minimally invasive option to the diagnosis of suspected myophosphorylase deficiency involves nonischemic forearm muscle exercise testing. Management includes avoidance of low-carbohydrate diets and low-to-moderate aerobic exercise.

Myophosphorylase deficiency is reviewed in detail here. Other GSDs and related disorders are reviewed separately. (See "Liver glycogen synthase deficiency (glycogen storage disease 0)" and "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)" and "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)" and "Lysosome-associated membrane protein 2 deficiency (glycogen storage disease IIb, Danon disease)" and "Glycogen debrancher deficiency (glycogen storage disease III)" and "Glycogen branching enzyme deficiency (glycogen storage disease IV, Andersen disease)" and "Liver phosphorylase deficiency (glycogen storage disease VI, Hers disease)" and "Phosphofructokinase deficiency (glycogen storage disease VII, Tarui disease)".)

A broader overview of GSD is also presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism".)

EPIDEMIOLOGY — Myophosphorylase deficiency has an estimated prevalence of 1:167,000 in the Spanish population [2]. The prevalence in the Dallas-Fort Worth, Texas area was estimated to be 1:100,000 [3].

PATHOGENESIS — Glycogen phosphorylase has an important role in glucose homeostasis and catalyzes the degradation of glycogen into glucose-1-phosphate by removal of alpha-1,4-glucoside residues from the outer branches of the glycogen molecule [4]. The degradation of glycogen continues until the peripheral branches of glycogen have been shortened to approximately 4 glucosyl units.

Glycogen phosphorylase exists in three distinct isozymes (muscle [PYGM], liver [PYGL], and brain [PYGB]), but diseases are only described for muscle and liver (see "Liver phosphorylase deficiency (glycogen storage disease VI, Hers disease)"). The muscle-specific symptoms of this disorder result from the inability to generate energy from muscle glycogen due to deficiency of the muscle isoform of phosphorylase. However, PYGM deficiency may cause other comorbidities since it is expressed in other tissues including the central nervous system, retinal pigment epithelium, immune system, kidney, and bone [5,6]. The effects of PYGM on galactose-1-phosphate levels may also result in posttranslational modifications of proteins through O-GlcNAcylation [5]. Cellular mechanical stress from increased muscle glycogen stores, downregulation of sodium-potassium pumps, and elevation of sarcoplasmic calcium leading to decreased cellular integrity can all result in rhabdomyolysis [7]. Oxidative stress and purine nucleotide metabolism may also contribute to muscle damage.

GENETICS — Myophosphorylase deficiency is an autosomal-recessive disorder due to mutations in the muscle isoform of phosphorylase (muscle glycogen phosphorylase [PYGM]), located at 11q13. Affected individuals have inherited a mutation in each copy of PYGM. This means each of an individual's parents will be an obligate carrier of one normal allele and one pathogenic allele. Thus, with each pregnancy, there is a 25 percent chance of the baby inheriting two alleles containing a pathogenic mutation and developing myophosphorylase deficiency, a 50 percent chance of inheriting one normal allele and one pathogenic allele (ie, an unaffected carrier), and a 25 percent chance of inheriting two normal copies of the gene and being unaffected and not a carrier.

Carriers of myophosphorylase deficiency do not become symptomatic. In a study of oxidative capacity and lactate production during maximal cycle exercise in 8 patients with myophosphorylase deficiency, 7 heterozygous carriers, and 11 healthy subjects, heterozygotes had maximal oxidative capacity and peak lactate responses identical to healthy subjects [8]. Previous reports of manifesting carriers of myophosphorylase deficiency have suggested pseudodominance, although this is likely attributable to the high carrier frequency of PYGM mutations and the lack of comprehensive DNA sequencing [8,9].

Numerous pathogenic mutations in PYGM have been described, although no genotype-phenotype correlations have been reported [4,7,10]. The most common mutation worldwide (in studied populations), but especially in affected White individuals in Europe and the United States, converts an arginine (R) residue to a stop codon (X) in exon 5 (p.R50X) [4]. Other common mutant alleles include p.G205S in these populations and the p.W798R mutation in the Spanish population [2]. The p.F710del is the most common in the Japanese population [4,11,12].

Two patients with compound heterozygosity (one of the common mutations on one allele and novel splicing mutations in introns 3 and 5 on the other allele) were both reported to have a milder phenotype with unusually high exercise capacity, probably related to the ameliorating effect of minimal myophosphorylase activity [13]. However, genotype-phenotype correlation has otherwise not been possible in myophosphorylase deficiency [14-16]. Nevertheless, the identification of these mutations has facilitated carrier detection and has proven diagnostically valuable.

The phenotype can be modulated by polymorphic variants of other genes. As an example, disease severity correlated with the genotype at the angiotensin-converting enzyme (ACE) locus. An insertion/deletion variant (the D allele) associated with modestly increased ACE activity was found more commonly in Spanish and Italian patients with more severe symptoms and reduced exercise tolerance [17,18].

CLINICAL FEATURES — Myophosphorylase deficiency usually presents in adolescence or early adulthood with exercise intolerance, fatigue, myalgia, cramps, poor endurance, muscle swelling, and fixed weakness [1]. Typical laboratory findings include myoglobinuria and elevated creatine kinase (CK). The presentation is somewhat different in older adults and very young children. Older patients may present with progressive weakness without history of cramps or myoglobinuria [19,20]. Myophosphorylase deficiency has also been reported in young children. Four children presented at or shortly after birth with respiratory insufficiency, generalized weakness, and hypotonia that led to death in infancy [21,22]. Another child (14 months old) presented with transient elevation of CK that was observed only during febrile episodes [23].

Muscular involvement — All patients with myophosphorylase deficiency develop muscle stiffness, pain, and/or weakness that can be induced by either brief periods of intense isometric exercise (eg, weight lifting) or by less intense but sustained dynamic exercise (eg, jogging). The degree of muscular involvement is variable in affected patients, but exercise intolerance worsens over time in most patients with myophosphorylase deficiency.

A "second wind" phenomenon, an improvement in myalgias, muscle stiffness, initial fatigue, and tachycardia after approximately 10 minutes of exercise, is experienced by patients with myophosphorylase deficiency. This "second wind" can be explained by increased blood flow, enhanced delivery of free fatty acids with concurrent activation of fatty acid metabolism [24], and also increased hepatic glucose utilization. A study of the Spanish myophosphorylase deficiency registry reported 86 percent repeatedly experienced this phenomenon during their life [2].

In one study of 112 patients with myophosphorylase deficiency, fixed weakness affecting proximal more than distal muscles (which was more often noted in older patients) was noted in 28 percent [20]. In another study of 80 patients with myophosphorylase deficiency, permanent weakness was noted in 11 percent of subjects after the age of 40 years [25]. In the Spanish national registry of 239 cases, 99.5 percent reported exercise intolerance [2]. A case-control study found that young adult patients with myophosphorylase deficiency have lower lean mass, bone mineral content, and bone density than controls [26]. However, these differences largely disappeared when comparing physically active patients with controls, suggesting that regular physical activity can prevent these changes.

The characteristics of muscle pain were examined in 24 patients with McArdle disease [27]. Pain was intermittent and exercise induced in 15 of the 23 patients who reported pain. However, in eight patients, permanent pain was a major clinical symptom, albeit not related to age or disease duration.

Acute kidney injury — Intense or prolonged exercise can lead to rhabdomyolysis. In more severe cases, this can lead to release of myoglobin from muscle tissues. Myoglobin is excreted in the urine and can cause kidney damage. In the Spanish national registry, acute kidney injury was reported in 4 percent, and one case of chronic kidney failure was reported [2]. In a study in the United Kingdom, myoglobinuria was seen in 62 percent and acute kidney injury in 11 percent [28]. (See 'Laboratory findings' below and "Rhabdomyolysis: Clinical manifestations and diagnosis".)

Laboratory findings — The most common laboratory findings are myoglobinuria and an elevated CK. Recurrent episodes of myoglobinuria occur in over 50 percent of patients [2,28]. At rest, the serum CK is usually elevated in most patients, with 99 percent having a CK level >200 units/L and 79 percent >1000 units/L in one series [2]. Increased levels of CK are observed even between episodes of myoglobinuria in patients with myophosphorylase deficiency. By comparison, the resting CK is usually normal in carnitine palmitoyltransferase type 2 deficiency, a common disease in the differential diagnosis of myophosphorylase deficiency. (See "Specific fatty acid oxidation disorders", section on 'Carnitine palmitoyltransferase type 2 deficiency'.)

Electromyography — The surface electromyogram (EMG) is abnormal in patients with myophosphorylase deficiency.

EMG is not needed for diagnosis, and findings are nonspecific. However, EMG may be obtained in patients with progressive or static muscle weakness who do not have cramps, pain, "second wind" phenomenon, and/or myoglobinuria and in whom metabolic myopathy may not be suspected.

Nuclear magnetic resonance spectroscopy — In a study of patients with neuromuscular disorders, 31P-nuclear magnetic resonance spectroscopy (MRS) was abnormal in myophosphorylase deficiency [29]. Affected patients exhibited a lack of cellular acidification during ischemic exercise and a significant drop of the PCr/Pi ratio. 31P-nuclear MRS is a nonvalidated research test and is not widely available.

DIAGNOSIS — Myophosphorylase deficiency is suspected on the basis of a history of exercise-induced symptoms that are often associated with elevations of creatine kinase (CK), rhabdomyolysis, and myoglobinuria, although these are nonspecific. Misdiagnosis is common, with patients often labelled as "unfit," having "growing pains," or having other psychological conditions, rheumatic disorders, or other neuromuscular disorders. This leads to inappropriate treatment recommendations and an average diagnostic delays of 29 years [30]. A variety of tests may be helpful in confirming the diagnosis. Sequencing of PYGM is readily available and is the most efficient and least invasive means of confirming the diagnosis following detection of clinical symptoms and abnormal laboratory findings. Consultation with a clinical geneticist or a clinical biochemical geneticist may be helpful.

A minimally invasive approach to the diagnosis of suspected myophosphorylase deficiency, if the clinical history is not clear, can involve initial forearm muscle exercise testing. This is then followed by genetic testing if the results are suggestive of myophosphorylase deficiency. A more invasive approach is to proceed to muscle biopsy with biochemical or histochemical analysis that includes testing for myophosphorylase. In the case of an abnormal muscle biopsy result, genetic testing is necessary to confirm any findings. (See 'Genetics' above.)

Genetic testing — Molecular genetic testing of PYGM is routinely available in clinical laboratories for sequencing of the entire coding region and for duplication and deletion analysis. Next-generation sequencing panels often include myophosphorylase deficiency within larger myopathy panels. However, given the variable frequency of PYGM mutations in different populations, the ethnic background of the patient should be taken into consideration to appropriately target testing for common mutations. The use of next-generation sequencing panels or whole-exome sequencing is growing and is indicated for first-line testing in highly heterogenous presentations such as nondifferentiated hyperCKemia [31]. Muscle histopathology may be helpful in evaluating variants of unknown significance detected on sequencing. (See 'Genetics' above and "Next-generation DNA sequencing (NGS): Principles and clinical applications" and 'Histology' below.)

Forearm exercise test — The preferred forearm exercise test is a nonischemic [32], or minimally ischemic, test [8]. This test typically consists of having the patient perform maximal effort, one-second handgrips every other second for one minute (approximately 30 contractions). Blood samples for lactate, ammonia, and CK are taken before starting the test and at 1, 2, 4, 6, 10, 20, and 30 minutes after the end of the exercise. A flat venous lactate curve with normal increases in ammonia is consistent with the diagnosis of myophosphorylase deficiency. The test should be discontinued if the patient complains of muscle pain and/or cramps during the exercise, although this is uncommon if the test is performed properly. The forearm ischemic test, which involves the inflation of a blood pressure cuff to cut off circulation, is no longer recommended, because it triggers muscle pain and cramps and may cause acute compartment syndrome [33].

Histology — Histochemical staining for myophosphorylase in muscle frozen sections reveals no activity in muscle fibers in most cases. In some patients, however, there may be up to 10 percent of normal residual enzyme activity [34,35]. Myophosphorylase activity may also be detected on histochemical testing in muscle biopsies with a significant number of regenerating fibers because of the existence of a fetal isozyme immunologically different from mature muscle phosphorylase in these fibers [19]. Regenerating fibers usually are numerous in muscle biopsy specimens after an episode of myoglobinuria. Thus, a muscle biopsy performed shortly after an episode of rhabdomyolysis may provide a false-positive histochemical reaction for myophosphorylase [36].

Enzymatic testing of myophosphorylase activity and glycogen content is clinically available from fresh-frozen muscle biopsy samples. Myophosphorylase activity is normal in erythrocytes, platelets, and cultured skin fibroblasts from patients with McArdle disease, a finding probably related to the existence of nonmuscle isozymes.

The muscle biopsy in myophosphorylase deficiency may also reveal focal subsarcolemmal and intermyofibrillar accumulations ("blebs") of normally structured glycogen. The amount of glycogen is either normal or moderately increased to approximately twice normal.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of myophosphorylase deficiency includes the other GSDs and lysosomal defects that affect skeletal muscle. The key features of these disorders and diagnostic testing are reviewed in the table (table 1). (See "Overview of inherited disorders of glucose and glycogen metabolism" and "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)" and "Lysosome-associated membrane protein 2 deficiency (glycogen storage disease IIb, Danon disease)".)

Additionally, similar myopathic symptoms can be seen in myoadenylate deaminase deficiency, long-chain fatty acid oxidation disorders including carnitine palmitoyl transferase 2 deficiency and very long-chain acyl-CoA dehydrogenase deficiency, and mitochondrial myopathies. (See "Approach to the metabolic myopathies" and "Metabolic myopathies caused by disorders of lipid and purine metabolism" and "Mitochondrial myopathies: Clinical features and diagnosis" and "Overview of fatty acid oxidation disorders" and "Specific fatty acid oxidation disorders".)

Symptoms suggestive of other forms of myopathies can be difficult to distinguish but may include a history of hypoketotic hypoglycemia or cold sensitivity in some fatty acid oxidation disorders. Forearm exercise testing may help in differentiating myoadenylate deaminase deficiency from myophosphorylase deficiency through an insufficient rise in ammonia with normal elevations of lactate. Biochemical testing for these other myopathies minimally should include plasma ammonia, plasma acylcarnitines, plasma total and free carnitine levels, blood glucose, blood and urine beta-hydroxybutyrate and acetoacetate (ketone) levels, and urine organic acids during periods of clinical symptoms. Diagnostic sequencing of the myophosphorylase gene PYGM or the genes of the other forms of myopathies is clinically available, often as larger next-generation DNA sequencing panels that include all of these genes, and is often necessary to distinguish these disorders. (See 'Genetics' above and "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

TREATMENT — Trials investigating therapies for myophosphorylase deficiency have suffered from small numbers. Minimal benefit has been seen with a carbohydrate-rich diet, oral sucrose (such as in sports drinks), and low-dose creatine (60 mg/kg/day) with regard to exercise tolerance, but no effect has been demonstrated with D-ribose, glucagon, verapamil, vitamin B6, branched-chain amino acids, dantrolene sodium, aminoglycosides (eg, gentamicin), or high-dose creatine (150 mg/kg/day) [37,38]. One study suggested that treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril was beneficial [39]. Use of this therapy was based upon the observation that increasing copies of the D allele of the ACE locus was associated with disease severity, especially in women. However, the potential adverse effects (eg, weight gain, rhabdomyolysis, increased myalgias) are not fully elucidated, and no further studies on this therapy have been published.

Gradually applied moderate physical activity, together with preexercise dietary measures, may be beneficial in decreasing exercise-related symptoms [40].

Diet — Higher-carbohydrate diets may lead to some improvement in patients with myophosphorylase deficiency by maintenance of hepatic glycogen stores that support mobilization of hepatic glucose during exercise [38,41]. Low-carbohydrate diets that are high in fat and/or protein have not been found to be beneficial beyond isolated reports [42]. Consumption of simple carbohydrates (eg, sucrose) before dynamic/aerobic exercise may improve exercise tolerance and decrease the risk of exercise-induced rhabdomyolysis. However, sucrose supplementation is not likely to prevent muscle damage from exercise that is static (eg, weight lifting) or unanticipated, has the potential to cause weight gain, and could interfere with mobilizing lipid stores during prolonged exercise.

The potential benefits of oral sucrose administration were demonstrated in a trial that assigned 12 patients with McArdle disease, in random order, to either sucrose (75 grams) or an artificially sweetened placebo solution in 660 mL of beverage [43]. Patients served as their own controls and exercised by cycling at a constant workload (50 watts). Exertion was significantly better tolerated after drinking the sucrose solution. Peak heart rates were lower (by a mean of 35 beats per minute), and the patients' perceptions of the amount of exertion were also less than with placebo.

A similar trial in six patients compared two sucrose regimens (75 grams 40 minutes before exercise and 37 grams 5 minutes before exercise) with placebo [44]. Both sucrose regimens were associated with decreased peak heart rate, improved exercise tolerance, and lack of a "second wind" phenomenon, but perceived exertion and heart rate were consistently lower when sucrose was administered five minutes before exercise.

The Spanish registry reported that patients with active physical activity patterns typically consumed a carbohydrate sports drink (approximately 26 g carbohydrate in 330 mL) before exercise and then for each hour of exercise [2].

In one randomized trial, a diet containing 65 percent carbohydrate, 20 percent fat, and 15 percent protein showed improvements in heart rate, work effort, and exercise tolerance [38,41]. Other trials of a ketogenic diet or using oral supplementation of exogenous ketone bodies (poly-hydroxybutyrate) are underway [45-47].

Oral administration of glucose or fructose has not resulted in consistent improvement and has caused significant weight gain. D-ribose or branched-chain amino acids have not improved exercise capacity. A trial of an odd-chain fatty acid, triheptanoin, also did not show any effect [48].

Exercise — Growing data suggest that mild-to-moderate aerobic exercise, such as walking, bicycling, or stationary cycling, is beneficial for patients with myophosphorylase deficiency in that it improves cardiovascular fitness and increases muscle oxidative capacity while avoiding anaerobic strenuous exercise [49-52]. However, further confirmation of benefit in larger controlled trials is needed, and the risk of rhabdomyolysis, if any, must be determined. Low-level warm-up before any planned moderate exercise may help minimize symptoms [40].

The benefits of routine moderate exercise were demonstrated in a series of eight patients with myophosphorylase deficiency who exercised by pedaling a stationary cycle for 30 to 40 minutes per session four times a week at 60 to 70 percent of maximal heart rate [49]. After 14 weeks of training, average work capacity, oxygen uptake, and cardiac output increased by 36, 14, and 15 percent, respectively, compared with pretraining levels. Exercise was well tolerated, and no patients developed pain, cramping, or increased serum creatine kinase (CK) levels related to the prescribed exercise. In a subset of nine patients following an eight-month intensive training period, peak oxygen uptake (VO2peak) showed a 44 percent improvement after training, placing participants into the low-normal range with normal controls [52]. No significant negative outcomes were reported.

Creatine — The benefit of dietary supplementation with creatine is not clear, and additional studies are needed before this therapy can be recommended for patients with myophosphorylase deficiency.

A double-blind, placebo-controlled, crossover study of the effects of low-dose (60 mg/kg per day) oral creatine supplementation in nine patients with myophosphorylase deficiency demonstrated an increase in ischemic isometric forearm exercise capacity but no improvement in nonischemic isometric exercise or in cycle exercise [53]. The effects appear to be dose limited since exercise tolerance worsened in response to the daily administration of high-dose creatine (150 mg/kg) in a follow-up study [54].

OTHER MANAGEMENT ISSUES

General anesthesia — Severe perioperative problems are rare [55]. Patients with McArdle disease do not appear to have increased susceptibility to malignant hyperthermia. However, general anesthesia, particularly with succinylcholine and volatile anesthetics, has the potential to cause acute rhabdomyolysis that can result in myoglobinuria and even acute kidney injury [56]. Management is discussed separately. (See "Rhabdomyolysis: Clinical manifestations and diagnosis" and "Susceptibility to malignant hyperthermia: Evaluation and management", section on 'Enzymopathies of skeletal muscle'.)

Statins — There are several case reports of statin-induced myopathy, including severe rhabdomyolysis, in patients with McArdle disease and carriers of mutations that cause metabolic myopathies [57-60]. Thus, this class of lipid-lowering drugs should be used with caution in these populations. (See "Statin muscle-related adverse events" and "Statins: Actions, side effects, and administration" and "Drug-induced myopathies".)

Pregnancy — The risk of complications during childbirth and delivery does not appear to be increased in women with McArdle disease [28].

SUMMARY AND RECOMMENDATIONS

Myophosphorylase (muscle phosphorylase) deficiency, also historically known as glycogen storage disease V (GSD V) or McArdle disease, is an autosomal-recessive disease caused by mutations in the muscle glycogen phosphorylase (PYGM) gene. The frequency of specific mutations varies depending upon the ethnic background of the patient. In myophosphorylase deficiency, glycogen is not properly broken down in muscle cells, interfering with their function. (See 'Introduction' above and 'Pathogenesis' above and 'Genetics' above.)

Myophosphorylase deficiency usually presents in adolescence or early adulthood with exercise intolerance, fatigue, myalgia, cramps, myoglobinuria, poor endurance, muscle swelling, and fixed weakness. However, symptoms are often seen in childhood and may be misdiagnosed for decades. (See 'Clinical features' above.)

Myophosphorylase deficiency is suspected on the basis of the history of exercise-induced symptoms. Genetic testing is the most efficient and least invasive means of confirming the diagnosis in patients with clinical findings consistent with the diagnosis. A minimally invasive approach to the diagnosis, with a nonischemic forearm exercise test, is usually taken in patients who do not have a clear clinical history. Muscle biopsy with histochemical and biochemical testing for myophosphorylase should only be performed when DNA sequencing is inconclusive. (See 'Diagnosis' above.)

A carbohydrate-rich diet may be of benefit for patients with myophosphorylase deficiency. (See 'Diet' above.)

We suggest the preexercise ingestion of a simple carbohydrate (eg, sport drink) approximately five minutes before all types of dynamic/aerobic exercise (Grade 2C). (See 'Diet' above.)

Patients with myophosphorylase deficiency should perform regular mild-to-moderate physical activity under medical supervision with the guidance of a well-trained fitness specialist, with a low-level warm-up before any planned moderate exercise. (See 'Exercise' above.)

The benefits of creatine supplementation, treatment with angiotensin-converting enzyme (ACE) inhibitors, and vitamin B6 supplementation for patients with myophosphorylase deficiency remain unproven. (See 'Treatment' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Basil T Darras, MD; William J Craigen, MD, PhD; and J Lawrence Merritt II, MD, who contributed to an earlier version of this topic review.

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Topic 2909 Version 17.0

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