Glycogen Storage Disease Type V (GSD V)

At a glance

Autosomal recessive inherited inborn error of metabolism with an onset usually noticed in childhood. It is often not diagnosed until the third or fourth decade of life. Symptoms include exercise intolerance with muscle pain, early fatigue, painful cramps, and myoglobin in the urine (often provoked by exercise). Severe rhabdomyolysis leading to myoglobinuria is present. Patients may present at emergency rooms with severe fixed muscular contractures and severe pain. These require urgent assessment for rhabdomyolysis that is present in 30% of cases and consequently leads to acute renal failure. Left untreated this is life-threatening. In a small number of cases, Compartment Syndrome may develop, requiring prompt surgical referral.

Synonyms

McArdle Disease; McArdle Syndrome; McArdle Myopathy; Muscle Glycogen Phosphorylase Deficiency; Myophosphorylase Deficiency; Glycogenosis Type V.

History

This inborn error of metabolism was first described in 1951 by Brian McArdle (1911-2002), a British pediatrician, in a 30-year-old man who complained of pain followed by weakness and stiffness after exercise.

Incidence

GSD V accounts for approximately 2.5% of all patients affected with GSD worldwide. Its incidence is reported as 1 in 100,000.

Genetic inheritance

Autosomal recessive. Although males and females should be equally affected, more males than females have been reported. The gene encoding the muscular isoform of phosphorylase is located on band 11q13. Nonsense, deletion, missense, and splice-junction mutations usually result in almost complete absence of myophosphorylase in skeletal muscle. Three common mutations in genes (R49X, G204S, K542T) account for approximately 90% of the mutant alleles in the white population.

Pathophysiology

Deficiency of muscle phosphorylase (myophosphorylase or alpha-1,4-glucan orthophosphate glycosyl transferase), which initiates glycogenolysis by removing 1,4-glucosyl groups with release of glucose-1-phosphate. Myophosphorylase is the only isoform present in skeletal muscle (but also in the heart and the brain). Patients are unable to release glucose from glycogen in muscle. The production of adenosine triphosphate via the Krebs cycle is compromised and the exercising muscle derives its energy from blood glucose and free fatty acids, which might account for the second-wind phenomenon experienced by these patients, (ie, progressive fatigue and muscle weakness develops after 10 to 15 minutes of exercise. Following a rapid recovery, exercise can be resumed without difficulties for a prolonged time period).

Diagnosis

Painful muscle cramps following exercise. No rise in serum lactate following ischemic exercise. Phosphorus-31 nuclear magnetic resonance (³¹P-NMR) shows a lack of cytoplasmic acidification following exercise. DNA diagnosis possible. No electrical activity may be observed on electromyography (EMG) during cramps. The disease may be asymptomatic during childhood.

Clinical aspects

Clinical heterogeneity. The onset of the disease is often in adolescence or early adulthood. Muscle weakness and cramping of skeletal ...