Background

• McArdle disease, also called as glycogen storage disease type V (GSD V) or myophosphorylase deficiency, is a rare genetic disorder that affects muscle metabolism. It is an autosomal recessive disorder, meaning an affected individual inherits two copies of the defective gene, one from each parent. Myophosphorylase deficiency prevents muscle cells from breaking down glycogen into glucose-1-phosphate. 
• Glycogen is an essential muscle energy source during increased demand, such as exercise. However, in individuals with McArdle disease, the impaired myophosphorylase enzyme prevents the efficient breakdown of glycogen, leading to an inability to release glucose-1-phosphate. As a result, affected individuals have difficulty mobilizing glycogen stores and generating glucose for energy production within muscle cells. 

Epidemiology

• McArdle disease affects between 1 in 50,000 and 1 in 200,000 people in United States. However, the actual frequency is unknown. The difference between the prevalence based on genetic data and the frequency based on confirmed cases is due to the diagnosis delay.
• One research used gene frequency and data from next-generation sequencing to determine the disease’s incidence across populations. According to the study, the condition affects 1 in 7,650 people, much more than previously believed to have it (95% confidence interval [CI]). The two most prevalent mutations were the focus of a second approach utilized by the same research, which found a frequency of 1 in 42,355 cases. 

Anatomy

Pathophysiology

The pathophysiology of McArdle’s disease revolves around impaired glycogen metabolism and subsequent energy production in muscle tissue. 

• Glycogen Accumulation: In individuals with McArdle disease, myophosphorylase deficiency prevents the efficient breakdown of glycogen. As a result, glycogen accumulates within muscle cells, leading to the characteristic feature of increased muscle glycogen content. 
• Impaired Glycogenolysis: In McArdle disease, the lack of myophosphorylase activity hampers glycogenolysis, leading to an inability to release glucose-1-phosphate from glycogen stores. 
• Energy Depletion: The impaired breakdown of glycogen in McArdle disease reduces the availability of glucose-1-phosphate, essential for muscle cell energy production. This leads to a lack of glucose-derived energy during exercise or periods of increased muscle demand. 
• Energy Crisis and Symptoms: Without sufficient glucose-derived energy, affected individuals experience exercise intolerance, muscle pain, cramps, and fatigue.  
• Shift to Alternative Energy Sources: In response to the energy crisis caused by impaired glycogen breakdown, muscle cells in McArdle disease attempt to utilize alternative energy sources, such as fatty acids.  
• Release of Substances: During periods of muscle exertion, muscle fibers can be damaged, releasing substances into the bloodstream. In McArdle disease, this can result in the release of myoglobin, leading to myoglobinuria (the presence of myoglobin in the urine). Dark urine after exercise is a characteristic feature of McArdle disease. 

Etiology

• Role of Glycogen Phosphorylase (PGYM): The glycogen phosphorylase enzyme, encoded by the PYGM gene, plays a crucial role in the breakdown of glycogen in muscle tissue. Specifically, it is responsible for catalyzing the first step of glycogenolysis, which involves the release of glucose-1-phosphate monomers from glycogen stores in muscle fibers. 
• Mutations in the PYGM Gene: McArdle disease is caused by genetic mutations in the PYGM gene, resulting in a deficiency or absence of functional glycogen phosphorylase enzyme. These mutations can lead to various enzyme deficiencies, including reduced enzyme activity or complete enzyme inactivation. 
• Inactivation of Glycogen Phosphorylase: The genetic mutations in the PYGM gene can render the glycogen phosphorylase enzyme inactive. This inactivation prevents the efficient breakdown of glycogen into glucose-1-phosphate, impairing the muscle’s ability to utilize glycogen as an energy source during exercise or periods of increased energy demand. 
• Genetic Mutation Hotspots: Certain regions of the PYGM gene, such as exons 1 and 17, are considered hotspots for mutations associated with McArdle disease. Nonsense mutations, which result in the premature termination of protein synthesis, are widespread and account for approximately half of the identified mutations. 
• Prevalent Mutation: Among individuals of White ethnicity, the most prevalent mutation identified is p.Arg50Stop (also known as R50X). This mutation produces a truncated and non-functional glycogen phosphorylase enzyme, resulting in the characteristic features of McArdle disease. 

Genetics

Prognostic Factors

• Average Life Expectancy: McArdle disease does not typically affect life expectancy. Individuals with this condition can have an average lifespan with appropriate management and lifestyle modifications. 
• Prevention of Rhabdomyolysis: Rhabdomyolysis, characterized by muscle breakdown and release of myoglobin into the bloodstream, can lead to complications such as acute renal failure. Preventing episodes of rhabdomyolysis is essential to avoid potentially life-threatening complications. 
• “Second Wind” Phenomenon: Many individuals with McArdle disease experience the “second wind” phenomenon, where they initially struggle with exercise but can eventually continue with less difficulty. This phenomenon allows individuals to adapt and learn to live with the condition, optimizing their physical activities. 
• Clinical Severity Heterogeneity: McArdle disease can exhibit a range of clinical severity among individuals. Some may have no symptoms in everyday life, while others may experience difficulties in daily activities and fixed muscular weakness.  

Clinical History

Physical Examination

Muscle Examination: 

• Muscle weakness: There may be evidence of muscle weakness, particularly in the affected muscles. This weakness is often seen during physical activity or exercise. 
• Average muscle bulk: Unlike other muscle disorders, individuals with McArdle disease typically have average muscle bulk and no significant muscle wasting or atrophy. 
• Muscle stiffness or cramping: The muscles may exhibit stiffness or cramping, especially after exertion or during prolonged exercise. 

Neurological Examination: 

• Sensation and reflexes: Sensation and deep tendon reflexes are usually normal in McArdle disease unless other underlying neurological conditions are present. 
• Coordination and gait: Coordination and gait are typically unaffected in McArdle disease, as it primarily affects muscle metabolism rather than the neurological control of movement. 

Age group

Associated comorbidity

• Individuals with McArdle disease may have a history of exercise intolerance, muscle cramps, stiffness, and fatigue during physical activity. 
• Some individuals may experience recurrent muscle pain and stiffness episodes, especially during or following intense exercise. 
• Rhabdomyolysis (severe muscle breakdown) can sometimes occur, leading to myoglobinuria (presence of myoglobin in the urine) and potential complications such as acute renal failure. 

Associated activity

Acuity of presentation

The onset of symptoms in McArdle disease can range from acute to gradual. 

• Acute presentations may involve episodes of muscle pain, cramps, and weakness during or following physical activity, often resulting in the need to stop exercising. 
• Gradual presentations may involve a history of persistent exercise intolerance, fatigue, and difficulty maintaining physical activity levels over time. 
• In some cases, the initial symptoms may be misinterpreted or attributed to other causes, leading to a delay in diagnosis.

Differential Diagnoses

The differential diagnosis of McArdle disease includes several conditions: 

Other Glycogen Storage Disorders: 

• Pompe disease (Glycogen storage disease type II) 
• Cori disease (Glycogen storage disease type III) 
• Andersen disease (Glycogen storage disease type IV) 
• Abnormalities in glycogen metabolism characterize Tarui disease (Glycogen storage disease type VII). These disorders can present with muscle weakness, exercise intolerance, and elevated creatine kinase levels. 

Fatty Acid Oxidation Disorders: 

• Carnitine palmitoyltransferase II (CPT II) deficiency 
• Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency 
• Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency 

Mitochondrial Myopathies: 

• Myoclonic epilepsy with ragged red fibers (MERRF) 
• Kearns-Sayre syndrome (KSS) 
• Chronic progressive external ophthalmoplegia (CPEO)  

Other Metabolic Myopathies: 

• Phosphofructokinase (PFK) deficiency 
• Tarui disease (Phosphofructokinase deficiency)  

Muscle Channelopathies: 

• Myotonia congenita 
• Periodic paralysis  

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

• Patients with McArdle disease should avoid activities leading to severe muscle damage, such as intense exercise or prolonged fasting. 
• Regular, moderate-intensity exercise is encouraged to improve muscle metabolism and exercise tolerance. Patients should engage in activities that allow them to gradually build endurance and take advantage of the “second wind” phenomenon. 
• Adequate warm-up and stretching before exercise can help prevent muscle injury. 
• Pharmacological Treatment: 
• Some patients with McArdle disease may benefit from administering a pharmaceutical agent called oral sucrose. Taking oral sucrose before exercise or during episodes of muscle cramps can provide quick energy and improve exercise capacity. 
• Creatine monohydrate supplementation has shown potential benefits in improving muscle strength and exercise tolerance in some patients.

• There are currently no specific interventional procedures for the treatment of McArdle disease.
• However, prompt medical intervention, including intravenous fluid administration and monitoring, may be necessary for acute rhabdomyolysis. 

• Acute Phase: During acute muscle pain or rhabdomyolysis episodes, prompt measures should be taken to alleviate symptoms and prevent complications such as acute renal failure. Rest, hydration, and pain management may be necessary. 
• Maintenance Phase: Once the acute symptoms subside, patients should focus on maintaining a regular exercise routine and avoiding triggers for muscle damage. This includes following a balanced diet, ensuring adequate hydration, and gradually increasing exercise intensity and duration. 

Medication

Future Trends

Media Gallary

References

• McArdle Disease:ncbi.nlm.nih