McArdle disease, also known as glycogen storage disorder type V, is an inborn metabolic disorder characterized by a deficiency or complete absence of an enzyme called glycogen phosphorylase (or myophosphorylase). This disease is inherited in an autosomal recessive pattern and mainly affects skeletal muscles.
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 release glucose-1-phosphate monomers in muscle fibers. As a result, 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. Exons 1 and 17 particularly exhibit mutation hotspots, and half of the cases are nonsense mutations. The commonest mutation in White race individuals is described as p.R50X or R50X.
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. 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.
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 the glycogenolysis in the liver, and they bind 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).
To support the diagnosis, muscle tissue is biopsied and examined under a microscope. The hallmark findings suggestive of McArdle disease are glycogen deposits, absence of enzymes such as phosphorylase, or phosphofructokinase.
The most frequently reported symptom remains exercise 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 pronounced immediately after starting exercise and alleviate 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).
A unique feature associated with this disorder called “second-wind phenomenon” is seen in some patients and is characterized by improved symptoms after approximately 10 minutes of rest or aerobic exercise, brisk walking, for example.
McArdle disease usually presents in the second or third decade of life, but some cases have been reported at a relatively younger age in neonates and infants presenting with hypotonia, generalized muscle weakness, and even respiratory failure. Patients more than 40 years of age complain of weakness and wasting of muscles.
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. A sphygmomanometer cuff is used to perform this test, and isometric rhythmic exercises are done for one minute while it is inflated. The cuff is then released, and the levels of lactate and ammonia before and after inflation of cuff are compared with one another.
During normal circumstances, a three-fold rise in lactate and ammonia occurs, but lactate rise is remarkably low in glycolytic and glycogenolytic disorders. This ischemic test making use of sphygmomanometer cuff is obsolete now, and there is a recent consensus upon the use of non-ischemic forearm exercise tests to avoid unfavorable outcomes like rhabdomyolysis and compartment syndrome. Both ischemic and non-ischemic tests have a fairly high sensitivity and specificity, therefore a normal test result roles out the possibility of glycolytic/glycogenolytic defect.
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.
A definitive diagnosis is by muscle biopsy and genetic testing. Muscle biopsy (vastus lateralis or biceps brachialis) shows periodic acid Schiff-positive vacuoles of high glycogen content and absence of myophosphorylase, in addition to phosphorylase and phosphofructokinase. Genetic testing includes options of specific mutation analysis (most commonly R49X/R50X in the White population), and next-generation PYGM gene sequencing panels or 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 PGYM 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 that often yields normal findings.
There are no specific recommendations for the management of people with McArdle disease, and treatment mostly gears towards avoiding lifestyle activities that exacerbate the symptoms. Most patients adapt themselves by not engaging in strenuous exercise, but this may worsen the disease because serum CK rises during periods of inactivity. 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.
Certain dietary interventions which confer favorable effects include taking a sugary meal before planning exercise—for example, having a drink containing 75g sucrose 40 minutes before exercise alleviates typical 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.
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 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.
In general, 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 show increased lipids, and a mitochondrial myopathy shows ragged red fibers and cytochrome oxidase negative fibers. Specific mutation analysis reveals the most common mutations to be R49X, S113L, and m.3243A>G in McArdle disease, fatty acid oxidation disorders, and mitochondrial defects, respectively.
Most of the patients affected with McArdle disease lead a normal life, and it does not affect life expectancy. Patients exploit the second wind phenomenon and adjust to the disease itself. Only a minority of patients have known to experience progressive worsening of symptoms with advancing age and wasting, especially over the shoulder girdle and back muscles.
Patients with McArdle disease exhibit a stable disease course unless and until there is an event of intensive exercise resulting in severe contractures and acute rhabdomyolysis (muscle breakdown). This muscle breakdown causes the liberation of myoglobin (muscle protein) in blood and urine, and acute renal failure may follow consequently.
Upon diagnosis of the condition, it is essential to refer the patient to a clinical geneticist/genetic counselor. Annual surveillance includes routine physical examination and diet checks. Counseling consists of avoiding certain exercises, e.g., sustained hand grips exercises, weight lifting unless under specialists supervision, competitive ball games, running, exercises involving excessive jumping, strenuous swimming, and cycling.
GSD type V is an autosomal recessive disease, and patients should be made aware of its inheritance pattern and risk in future generations. Homozygous persons are symptomatic, while heterozygous individuals carry affected genes and transmit to their offspring.
A consultation with a genetic specialist is the utmost in such circumstances. Optional genetic testing could be offered to the relatives (particularly siblings) of an affected individual. The autosomal recessive inheritance means that the parents are the carriers of the disease and have mild symptoms to no symptoms at all. Each sibling carries a 1 in 4 chance of being affected, a 1 in 2 chance of being a carrier, and 1 in 4 chance of being unaffected and non-carrier.
Appropriate family planning is necessary for affected individuals, carriers, or individuals at high risk of being carriers. All available options require collaborative exploration with the patient, including information about prenatal testing and preimplantation genetic testing before becoming pregnant.
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