McArdle Disease

Etiology

McArdle disease typically results from mutations involving the muscle-specific isoform of the glycogen phosphorylase enzyme (abbreviated as PGYM). This enzyme plays a key role in the first step of glycogenolysis, that releases glucose-1-phosphate monomers in muscle fibers. As a result, the carbohydrate metabolism of the skeletal muscle is affected, and energy cannot be generated from the glycogen stores of muscles. The genetic mutations of the PYGM gene on 11q13 make the enzyme inactive.[6] Exons 1 and 17 particularly exhibit mutation hotspots; half of the cases are nonsense mutations. The commonest mutation in White individuals is described as p.Arg50Stop or R50X.[7][8]

From the study of the genetics of McArdle disease, 179 variants have been identified that together affect the PYGM gene. Missense mutations have been found to be the most common variants in European and US White populations (around 60% of all mutations). It has been reported that the majority of the patients do not have myophosphorylase, regardless of the type of mutation, such as missense, nonsense, insertion, deletion, and splicing.[9] This indicates the absence of myophosphorylase activity when there is a PYGM mutation, except for those rare cases where missense mutations result in preserved myophosphorylase activity and better phenotypes.[10]

Epidemiology

The exact prevalence of McArdle disease is not precisely known and appears to range from 1 in 50,000 to 1 in 200,000 in the United States. The variation between the prevalence according to genetic data and the prevalence according to diagnosed cases is attributable to the delay in making a diagnosis. One study analyzed gene frequency and next-generation sequencing data to report the true prevalence of the disease among populations. The results of that study revealed that the disease is much more common than previously thought and has a prevalence of 1 in 7,650 (95% confidence interval (CI) 1/5,362-1/11,108). An additional method used by the same study looked at the two most common mutations and recorded a prevalence of 1 in 42,355.[11][8]

In some areas of the USA, such as the Dallas/Fort Worth area, the prevalence of McArdle disease on the basis of genetic data is reported to be 1/100000.[12] A study in Spain reported the prevalence of diagnosed cases to be around 1/139543.[13]

In terms of gender, in McArdle disease, the following ratios of men to women have been noted:

• Spain 55:45[13]
• Italy 65:35[14]
• UK 50:50[15]

In terms of age, most McArdle disease cases present in the second or third decade of life. Wolfe et al. report a unique precedent of McArdle disease manifesting in a 73-year-old patient.[16] Felice and Pourmand also reported late presentations. Providers should consider the diagnosis of McArdle disease regardless of the age of presentation.[17][18]

Pathophysiology

Myophosphorylase is a key enzyme in the regulation of glucose metabolism in muscles. It detaches 1,4 glycosyl chains from glycogen and attaches inorganic phosphate to form glucose-1-phosphate. During glycogen breakdown, muscle cells generate glucose-1-phosphate in place of glucose, and due to the polar nature of the former molecule, it disintegrates intracellularly.

PYG is activated when phosphorylated by the enzyme phosphorylase kinase. Glucagon and adrenaline initiate glycogenolysis in the liver, binding to G-protein coupled receptors first. The signaling pathway behind this process involves the following steps: GPCRs (G-protein coupled receptors) - AC (adenylate cyclase) – cAMP (cyclic adenosine monophosphate) – PKA (protein kinase A) – PK (phosphorylase kinase) causing PYG activation. In contrast, PYG becomes inactivated when dephosphorylated by a different enzyme called protein phosphatase 1 (PP1).[7]

There are several tissue-specific isoforms of phosphorylase. Myophosphorylase is found in cardiac myocytes and the brain, and it is the only variant present in skeletal muscle. Most patients with McArdle disease lack myophosphorylase activity; therefore, they are unable to produce energy in the form of glucose by breaking down glycogen stores in muscles.[19]

During aerobic activity, such as walking, jogging, gentle swimming, or cycling, the skeletal muscle derives energy from free fatty acids by oxidizing them in the mitochondria via the beta-oxidation pathway to form acetyl-CoA. Acetyl-CoA is further metabolized via the Krebs cycle and the respiratory chain, leading to the production of adenosine triphosphate (ATP). During anaerobic activity, such as weightlifting or sprinting, the myophosphorylase of the skeletal muscle breaks down glycogen to glucose, which then enters the glycolytic pathway yielding ATP anaerobically.[20]

Histopathology

To support the diagnosis, muscle tissue is biopsied and examined under a microscope. The hallmark findings suggestive of McArdle disease are glycogen deposits and the absence of the enzyme myophosphorylase.[21]

Glycogen deposits appear under the sarcolemmal membrane at the periphery of myofibers. The collection of glycogen between myofibrils makes the myofibers look like vacuoles. The glycogen takes up periodic acid-Schiff (PAS). The absence of glycogen accumulation in muscle biopsy should not be taken as proof for the absence of McArdle disease, as the glycogen could be washed out in tissue processing.

Myophosphorylase histochemistry is easier to perform and has a good negative predictive value. Its absence is diagnostic for McArdle disease. However, providers must specifically request the testing of myophosphorylase.

History and Physical

The most frequently reported symptom remains physical activity intolerance. Other symptoms include painful muscle cramps, weakness, and fatigue. Muscle pain and stiffness sometimes can lead to painful contractures. All these symptoms are much more pronounced soon after starting activity and alleviated with exercise cessation. In cases of sudden, persistent muscle contraction during high-intensity exercise, severe muscle damage can occur, resulting in a massive release of muscle proteins, i.e., creatinine kinase (typical level >1,000 U/l) and myoglobin in blood, as well as myoglobinuria (excretion of myoglobin in urine) presenting as dark-colored urine. In rare instances, acute renal failure and catastrophic hyperkalemia can ensue from an episode of rhabdomyolysis (muscle breakdown).[22]

A unique feature associated with this disorder called the “second-wind phenomenon” is seen in most patients and is characterized by improved symptoms after approximately 10 minutes of gentle aerobic activity.[8]

McArdle disease usually presents in the first or second decade of life. Patients more than 40 years of age complain of weakness and wasting of muscles.[23][24][8][7][21]

Clinical heterogeneity is widely seen in McArdle disease. Some patients present with very mild symptoms, such as tiredness without cramps. On the other hand, progressive weakness ensues in the 6th or 7th decade of life. Contrary to this, fatal infantile McArdle syndrome, which is the severe and rapidly progressive form, appears shortly after birth.

Seizures have been described in 4% of patients.

Classic McArdle disease presents with the following examination findings:

• Proximal muscle weakness - most notable following exercise
• Fixed limb weakness - usually in the proximal muscle groups
• Muscle wasting

The fatal infantile variant can have the following examination findings:

• Hypotonia
• Diminished deep tendon reflexes

Evaluation

Initial assessment in suspected cases is done using a forearm exercise test. As the process of glycogenolysis is defective, no pyruvate and subsequent lactate are produced through normal pathways. Isometric rhythmic exercises are done for one minute, and the levels of lactate and ammonia before and after are compared.

During normal circumstances, a three-fold rise in lactate and ammonia occurs, but lactate rise is remarkably low in glycolytic and glycogenolytic disorders. The ischemic test making use of a sphygmomanometer cuff is obsolete now, and there is a recent consensus on the use of nonischemic forearm exercise tests to avoid unfavorable outcomes like rhabdomyolysis and compartment syndrome.[25] The test has fairly high sensitivity and specificity; therefore, a normal test result rules out the possibility of a glycolytic/glycogenolytic defect. Nonischemic forearm testing is equally diagnostic, with a lesser risk of compartment syndrome. These tests are performed in the same way but with no use of a blood pressure cuff.[26] The nonischemic test has a sensitivity of 100% and a specificity of 100% and 99.7%, respectively, as has been reported by a 2015 retrospective study.[27]

A characteristic feature of McArdle disease is the chronically elevated serum creatine kinase (CK) enzyme levels.

Graded exercise stress is done to demonstrate the second-wind phenomenon, often seen in patients with McArdle disease, and also to distinguish it from disorders of glycolytic pathways.

Muscle biopsy (vastus lateralis or biceps brachialis) shows periodic acid Schiff-positive vacuoles of high glycogen content and absence of myophosphorylase. Genetic testing includes options of specific mutation analysis (most commonly R50X in the White population), next-generation PYGM gene sequencing panels, myopathy panels, or whole-exome sequencing for particular glycogen-storage diseases. Typically, patients are diagnosed based on whether they are homozygous or compound heterozygous for PYGM pathogenic mutations. A study aimed to formulate a less invasive approach to diagnose the disease and found out PYGM expression in white blood cells by using antibodies.

Other tests done to support the findings are serum uric acid levels (high in about half of the cases), urinalysis for detecting pigmenturia, and electromyography, which often yields normal findings.[8][28][26][6][21]

Treatment / Management

The treatment is mostly geared towards avoiding lifestyle activities that exacerbate the symptoms. Patients may adapt to avoiding physical activity, but this may worsen the disease because serum CK rises with loss of aerobic fitness. It may also result in the decreased capacity of muscles to utilize alternate fuels to overcome the block in glycogenolysis. Moreover, there is a marked reduction in the expression of proteins needed for metabolism and calcium hemostasis in non-exercising muscles.

There is evidence proving the beneficial effects of moderate-intensity graded aerobic exercise therapy. Patients reported less significant exercise intolerance and earlier appearance of second wind with this intervention. A balanced weight-lifting approach also lessens the severity of symptoms in some patients.

Howell et al. proposed that sodium valproate could cause the up-regulation of the myophosphorylase enzyme. The findings of that study suggested that sodium valproate could be a potential management option for McArdle disease; however, more randomized trials are needed.[29](B3)

It has been noted that creatine may improve ATP storage and exercise tolerability. However, in a trial, high-dose creatine monohydrate resulted in poor exercise tolerance and a significant increase in exercise-induced myalgia. The investigators proposed an explanation that inadequate adaptation to better electromechanical efficacy results in excess muscle contractility during exercise and, thus, a resultant worsening of symptoms.[30](A1)

Certain dietary interventions that confer favorable effects include taking a sugary meal before planned exercise—for example, having a drink containing 37 g sucrose 5 minutes before exercise reduces initial symptoms of exercise intolerance. A diet rich in carbohydrates results in much better outcomes in comparison to a protein-rich diet. Other nutritional agents that were helpful for some patients but could not yield convincing outcomes during actual experimental studies include branched-chain amino acids, depot glucagon preparations, verapamil, dantrolene sodium, vitamin B6, high dose D-ribose, and high-dose creatine ingestion.[31][24][22][32][8][33](A1)

Differential Diagnosis

It is essential to distinguish McArdle disease from other glycogen storage disorders as well as other diseases inducing myopathy, particularly fatty acid oxidation defects, and mitochondrial myopathies.

McArdle disease demonstrates its symptoms at the very beginning of rigorous physical activity, whereas fatty acid oxidation defects (carnitine palmitoyltransferase II deficiency) and mitochondrial myopathies (Medium-chain acyl-CoA dehydrogenase deficiency) show symptoms much later with a longer duration of the exercise. Moreover, fatty acid oxidation defects manifest their symptoms under stressful states such as fasting, fever, and infections.

A noteworthy phenomenon occurring with McArdle disease is the second wind phenomenon (lesser perception of discomfort), and it does not occur in other conditions mimicking McArdle disease.

Patients with McArdle disease have chronically high serum creatine kinase levels. This enzyme may or may not be elevated in other glycogen storage diseases, fatty acid oxidation defects, and mitochondrial myopathies.

Generally, a carbohydrate-rich meal before exercise decreases the symptom severity in McArdle disease and fatty acid oxidation defects but does not prove helpful in mitochondrial myopathies and worsens symptoms in the glycolytic pathway disorder.

Muscle biopsy and genetic testing further delineate the difference between the disorders mentioned above. On biopsy, McArdle disease shows high glycogen content, carnitine palmitoyltransferase II deficiency shows increased lipids, and mitochondrial myopathy shows ragged red fibers and cytochrome oxidase negative fibers. Specific mutation analysis reveals the most common mutations to be R50X, S113L, and m.3243A>G in McArdle disease, fatty acid oxidation disorders, and mitochondrial defects, respectively.[21]

Prognosis

Most of the patients affected with McArdle disease lead a normal life, and it does not affect life expectancy. Rhabdomyolysis is to be avoided as it can lead to acute renal failure, which may potentially become life-threatening. Patients exploit the second wind phenomenon and adjust to the disease itself. Only a minority of patients have been known to experience progressive worsening of symptoms with advancing age and wasting, especially over the shoulder girdle and back muscles.[24]

More recent studies report heterogeneity in the clinical severity, such as 8% of patients are asymptomatic in daily life, and 21% show limitations in the activities of daily living and fixed muscle weakness.[13]The evidence also reiterates acquiring an active lifestyle, which is critical in patients with McArdle disease.[13]

It has also been reported in various studies that the disease does not adversely alter the course of pregnancy or childbirth.[22]

Complications

Rhabdomyolysis is an established complication of McArdle disease.[34] Acute renal failure may result from myoglobinuria after vigorous exercise. As with any patient having rhabdomyolysis, patients with McArdle disease should be monitored for the possible complications of electrolyte abnormalities, compartment syndrome, and metabolic encephalopathy.[35]