Glycogen storage disease due to phosphoglycerate mutase deficiency (ORPHA:97234)
A rare glycogen storage disease characterized by susceptibility to rhabdomyolysis complicated by episodes of exercise-induced muscle pain, cramping, and myoglobinuria. Tubular aggregates may be present on muscle biopsy.
Epidemiology
The prevalence of this disease is still unknown. Fewer than 50 cases were reported worldwide. About half of the identified cases are related to the p.W78X variant (most common in patients with African American ancestry) with the remaining cases coming from other ethnic groups in the United States, Europe, and the Middle East.
Clinical description
Glycogen storage disease due to phosphoglycerate mutase deficiency (also known as GSD type X) is characterized by exercise intolerance leading to rhabdomyolysis which manifests through muscle cramps and pain accompanied by acute renal symptoms such as myoglobinuria. In the majority of cases, intense physical exercise is accompanied by abnormal elevation of creatine kinase, which persists between exertional episodes. Some patients present with glycogen accumulation and tubular aggregates within the skeletal muscle cells on muscle biopsy. Due to low specificity of the symptoms, many patients remain undiagnosed.
Etiology
The disease is caused by homozygous or compound heterozygous variants of the PGAM2 gene which encodes the muscle isoenzyme of phosphoglycerate mutase (PGAM2), a terminal glycolysis enzyme. PGAM2 reversibly catalyzes the conversion reaction of 3-phosphoglycerate (3-PGA) to 2-phosphoglycerate (2-PGA), which is then further metabolized to produce pyruvate. During exercise, insufficient residual PGAM2 activity results in the inability to catabolize enough glucose to meet the increased energy needs of the muscle cells. This leads to a decrease in intracellular ATP levels and an increase in intracellular calcium levels which cause the breakdown of skeletal muscle (rhabdomyolysis), resulting in symptoms of muscle soreness, cramping, and dark urine.
Diagnostic methods
A patient presenting with exercise intolerance with episodes of rhabdomyolysis characterized by abnormal creatine kinase levels persisting after exercise, abnormally elevated aspartate aminotransferase and alanine aminotransferase levels (which are secondarily elevated in the setting of hyperCKemia), and detection of myoglobinuria, should raise suspicion of a metabolic myopathy. Forearm ischemic exercise test (FIET) will produce an abnormally low increase of lactate concentration. Skeletal muscle biopsy reveals tubular aggregates and may show glycogen accumulation. To establish the final diagnosis, the most reliable method is sequencing of PGAM2 for biallelic pathogenic or likely pathogenic variants.
Differential diagnosis
The differential diagnosis is based on a clinical picture of myalgia and includes beta-oxidation defects, mitochondrial diseases, and other glycogen storage diseases (GSD), particularly GSD type V and GSD type VII which share features of sensitivity to rhabdomyolysis with GSD type X, as well as a lesser increase in lactate production compared to the norm following exercise. Tubular aggregates visible on muscle biopsy are specific to GSD type X.
Genetic counseling
The transmission is autosomal recessive. Genetic counseling can be offered to at-risk couples to inform them of the 25% risk of transmission to offsprings.
Management and treatment
The management of the disease is adapted to the patient's symptoms. Patients should be informed that strenuous exercises can trigger episodes of rhabdomyolysis and myoglobinuria. Limitation of simple carbohydrates in the diet is of theoretical benefit; dietary therapy has not been systemically studied in GSD type X. Regular, low-intensity exercise under optimal hydration conditions may reduce the intensity of muscle symptoms. To date, there is no treatment that replaces or restores PGAM2 activity.
Prognosis
GSD type X is not thought to impact the longevity of affected individuals. It is important to recognize and treat episodes of rhabdomyolysis promptly should they occur, as rhabdomyolysis can lead to significant morbidity and mortality, including multiorgan failure, if left untreated.

                            Last update: 
                            September 2023


                            - Expert reviewer(s): 
                            Dr Benjamin COCANOUGHER  - Dr Priya KISHNANI  - Dr Rebecca KOCH