Phosphoglycerate mutase deficiency is a disorder that primarily affects muscles used for movement (skeletal muscles). Beginning in childhood or adolescence, affected individuals experience muscle aches or cramping following strenuous physical activity. Some people with this condition also have recurrent episodes of myoglobinuria. Myoglobinuria occurs when muscle tissue breaks down abnormally and releases a protein called myoglobin, which is processed by the kidneys and released in the urine. If untreated, myoglobinuria can lead to kidney failure.

In some cases of phosphoglycerate mutase deficiency, microscopic tube-shaped structures called tubular aggregates are seen in muscle fibers. It is unclear how tubular aggregates are associated with the signs and symptoms of the disorder.

Phosphoglycerate mutase deficiency is caused by mutations in the PGAM2 gene. This gene provides instructions for making an enzyme called phosphoglycerate mutase, which is involved in a critical energy-producing process in cells known as glycolysis. During glycolysis, the simple sugar glucose is broken down to produce energy.

The version of phosphoglycerate mutase produced from the PGAM2 gene is found primarily in skeletal muscle cells. Mutations in the PGAM2 gene greatly reduce the activity of phosphoglycerate mutase, which disrupts energy production in these cells. This defect underlies the muscle cramping and myoglobinuria that occur after strenuous exercise in affected individuals.

Normal Function

The PGAM2 gene provides instructions for making an enzyme called phosphoglycerate mutase. The version of phosphoglycerate mutase produced from this gene is found predominantly in skeletal muscle cells. (Skeletal muscles are the muscles used for movement.) Another version of this enzyme, which is produced from a different gene, is found in many other cells and tissues.

Phosphoglycerate mutase is involved in a critical energy-producing process known as glycolysis. During glycolysis, the simple sugar glucose is broken down to produce energy. Phosphoglycerate mutase helps carry out a chemical reaction that converts a molecule called 3-phosphoglycerate, which is produced during the breakdown of glucose, to another molecule called 2-phosphoglycerate.

Health Conditions Related to Genetic Changes

Phosphoglycerate mutase deficiency

At least five mutations in the PGAM2 gene have been found to cause phosphoglycerate mutase deficiency. The most common of these mutations, written as Trp78Ter or W78X, replaces the protein building block (amino acid) tryptophan with a premature stop signal in the instructions for making phosphoglycerate mutase. This mutation results in the production of an abnormally short, nonfunctional version of the enzyme. Other mutations change single amino acids in phosphoglycerate mutase.

Mutations in the PGAM2 gene greatly reduce the activity of phosphoglycerate mutase, which disrupts energy production in skeletal muscle cells. This defect underlies the muscle cramping, muscle breakdown, and related signs and symptoms that occur following strenuous exercise in affected individuals.

Other Names for This Gene

• BPG-dependent PGAM 2
• GSD10
• MGC88743
• muscle-specific phosphoglycerate mutase
• PGAM-M
• PGAM2_HUMAN
• PGAMM
• phosphoglycerate mutase 2 (muscle)
• phosphoglycerate mutase isozyme M

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the PGAM2 gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. However, people who carry one altered copy of the PGAM2 gene may have some features of phosphoglycerate mutase deficiency, including episodes of exercise-induced muscle cramping and myoglobinuria.

Phosphoglycerate mutase deficiency is a rare condition; about 15 affected people have been reported in the medical literature. Most affected individuals have been African American.