Glycogen storage disease type V (GSDV) is an autosomal recessive disorder more commonly known as McArdle disease. This disease was originally described by Brian McArdle in 1951, hence the association of his name with the disease. The disease was seen in a 30-year-old patient who was suffering from muscle weakness, pain and stiffness following slight exercise. It was observed that blood lactate fell in this patient during exercise instead of the normal rise that would be seen. This indicated the patient had a defect in the ability to convert muscle glycogen to glucose and ultimately lactate. The identification that the deficiency causing these symptoms was the result of a muscle phosphorylase defect was not made until 1959. Glycogen phosphorylase (most commonly just called phosphorylase) exists in multiple tissue-specific isoforms. The muscle, brain and liver forms are encoded by separate genes. The muscle form is the only isozyme found expressed in mature muscle.
The gene for muscle phosphorylase (symbol PYGM) is located on chromosome 11q12–q13.2 and is composed of 20 exons and directs the synthesis of two alternative splice variant mRNAs. Isoform 1 encodes a protein of 842 amino acids and isoform 2 encodes a protein of 754 amino acids. The muscle isoforms represent about 50% of total phosphorylase in cardiac muscle, 30% of the brain phosphorylase, and is completely absent from the liver. At least 14 different mutations have been identified as causing GSDV The most commonly encountered mutation (75% of patients) is a nonsense mutation that changes a C to a T in exon 1 converting an arginine codon to a stop codon (R49X).
The clinical presentation of GSDV is usually seen in young adulthood and is characterized by exercise intolerance and muscle cramps following slight exercise. Attacks of myoglobinuria frequently accompany the muscle symptoms of GSDV. About half of GSDV patients will exhibit burgundy colored urine after exercise. Diagnosis of muscle glycogenoses such as GSDV can be made by the observation of a lack of increased blood lactate upon ischemic exercise testing. In addition, there will be an associated large increase in blood ammonia levels. In order to distinguish GSDV from other muscle defects along the pathway from glycogen to glucose to lactate, an enzymatic evaluation of muscle phosphorylase must be done. Also, molecular analysis for known mutations in the muscle phosphorylase gene can be accomplished using DNA extracted from leukocytes.