Metabolic Myopathy

• Myopathy Due to Glycogen Storage Disease

Myopathy Due to Glycogen Storage Disease

Introduction

Glycogen storage diseases (GSDs) are a group of inherited metabolic disorders characterized by defects in glycogen metabolism. Myopathy due to GSD primarily affects skeletal muscles, resulting in exercise intolerance, muscle weakness, and other related symptoms. These conditions are caused by enzymatic deficiencies that impair glycogen synthesis, breakdown, or utilization, leading to muscle glycogen accumulation or energy production deficits.

History

The first descriptions of GSD-related myopathies date back to the early 20th century. In 1928, von Gierke identified GSD type I, while McArdle described GSD type V in 1951, highlighting exercise-induced muscle symptoms. Advances in biochemical and genetic techniques have since allowed the classification of GSD into various subtypes based on the specific enzyme defect and clinical presentation.

Epidemiology

GSDs are rare disorders, with an estimated incidence of 1 in 20,000 to 25,000 live births. Some myopathic forms, such as GSD type V (McArdle disease) and GSD type VII (Tarui disease), represent a smaller fraction. GSDs display autosomal recessive inheritance patterns, with some mitochondrial and autosomal dominant exceptions. 

Pathophysiology

GSD-related myopathies arise from enzymatic deficiencies in glycogen metabolism, resulting in impaired glycogen breakdown or utilization.

• GSD Type II (Pompe Disease): Acid maltase deficiency leading to lysosomal glycogen accumulation and muscle damage,
• GSD Type V (McArdle Disease): Myophosphorylase deficiency prevents glycogen breakdown during exercise.
• GSD Type VII (Tarui Disease): Deficiency of phosphofructokinase, affecting glycolysis and energy production. 

The underlying metabolic dysfunction results in muscle weakness, cramps, and fatigue due to insufficient available energy during exertion.

Clinical Manifestations

Exercise intolerance often presents with early fatigue. Muscle cramps and pain are common, especially during anaerobic exercise. Strenuous activity may lead to myoglobinuria, which causes dark urine. Muscle weakness can be proximal or generalized, with some cases showing progressive muscle atrophy. Certain conditions, like McArdle disease, exhibit a second wind phenomenon, while others, such as Pompe disease, may involve the cardiac and respiratory systems.

Diagnosis

• Clinical history and physical examination
• Serum creatine kinase (CK) levels Exercise tests (e.g., ischemic forearm test)
• Muscle biopsy (showing glycogen accumulation or enzyme deficiency)
• Enzyme activity assays Genetic testing for specific mutations
• Electromyography (EMG) and MRI for muscle involvement

Treatment

• Lifestyle modifications: Avoidance of strenuous exercise and fasting 
• Dietary interventions: High-protein or high-carbohydrate diets in specific subtypes 
• Pharmacological therapies: Enzyme replacement therapy in Pompe disease, vitamin B6 in GSD type V 
• Exercise programs: Aerobic training and supervised exercise to improve oxidative metabolism 
• Supportive care: Pain management, physical therapy, and monitoring of respiratory and cardiac function 

Prognosis

The prognosis of GSD-related myopathy varies depending on the subtype and severity of the enzyme deficiency. McArdle disease typically presents with a benign course, while Pompe disease can lead to life-threatening cardiopulmonary complications. Early diagnosis and appropriate management significantly improve the quality of life and reduce morbidity in affected individuals. Future advancements in gene therapy, enzyme replacement, and metabolic interventions hold promise for improving outcomes in patients with GSD-related myopathies.