Glycogen Storage Disease Type V (GSD V)

Autosomal recessive inherited inborn error of metabolism, probably underdiagnosed, characterized by muscle fatigue, myalgia, and cramping following exercise.

McArdle Disease (or Syndrome, or Myopathy); Muscle Glycogen Phosphorylase Deficiency; Myophosphorylase Deficiency; Glycogenosis type V.

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.

GSD V accounts for approximately 2.5% of all patients affected with GSD worldwide.

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 the gene (R49X, G204S, K542T) account for approximately 90% of the mutant alleles in the white population.

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, (i.e., progressive fatigue and muscle weakness develops after 10 to 15 min of exercise. Following a rapid recovery, exercise can be resumed without difficulties for a prolonged time period.)

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 EMG during cramps. The disease may be asymptomatic during childhood.

Clinical heterogeneity. Onset often in adolescence or early adulthood. Weakness and cramping of skeletal muscles after exercise. May have episodes of rhabdomyolysis and myoglobinuria after vigorous exercise (half of patients develop acute renal failure). Muscle wasting develops later. Heart muscle unaffected. Prognosis generally good with avoidance of excessive exercise. Seizures have been described in 4% of patients. A rare fatal infantile form is described (hypotonia, diminished tendon reflexes); death results from respiratory failure as a consequence of severe muscular weakness. A late-onset form, also very rare, has been reported.

Assess history for episodes of myoglobinuria and severity of episodes of muscle weakness. Check renal function, which may be impaired by myoglobinuria. Patients with GSD V may be depleted in pyridoxine, which is normally bound to myophosphorylase.

Tourniquets may lead to prolonged muscle cramping, even compartment syndrome, and should be avoided. Maintain normothermia to prevent shivering in the postoperative period. Dextrose-containing solutions should be infused perioperatively.

Succinylcholine should be avoided because of the risk of severe myoglobinuria. Nondepolarizing muscle relaxants have been used without problems, although reduced doses may be required (nerve stimulator).

Other glycogen storage diseases.