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Glycogen storage disease due to phosphoglycerate kinase 1 deficiency
A rare inborn errors of metabolism characterized by variable combinations of non-spherocytic hemolytic anemia, myopathy, and various central nervous system abnormalities.
ORPHA:713Classification level: Disorder
Phosphoglycerate kinase (PGK) deficiency prevalence is unknown but about 30 unrelated affected families have been reported so far.
The majority of patients present with chronic hemolytic anemia, which may be severe in some cases. Myopathy is a common finding and is characterized by exercise-intolerance, muscle weakness, cramping, myalgia and episodes of myoglobinuria. Rhabdomyolysis has also been reported in a few patients. Intellectual deficit is frequent, and other central nervous system manifestations may be also present including hemiplegic migraines, epilepsy, ataxia and tremor. Only a few patients show all three cardinal features of the disorder (hemolytic anemia, central nervous system abnormalities and myopathy), and several cases of PGK deficiency with myopathy in the absence of hemolytic anemia have been reported. Only one asymptomatic patient has been described with mild PGK deficiency.
PGK deficiency is caused by mutations in the PGK1 gene (Xq13.3) and around 20 different disease-causing variants have been identified so far in affected families. PGK is a key enzyme in the glycolytic pathway catalyzing the conversion of 1,3-bisphosphoglycerate into 3-phosphoglycerate and generating ATP. PGK is a ubiquitous enzyme expressed in all tissues except the testes.
Diagnosis is made on the basis of the clinical picture, together with biochemical studies revealing low erythrocyte and muscle PGK enzyme activity (below 23% and 25% of normal respectively), and identification of PGK1 gene mutations by molecular analysis.
The differential diagnosis should include other causes of hereditary non-spherocytic hemolytic anemia.
Molecular prenatal diagnosis is feasible for families of an index case.
PGK deficiency is inherited as an X-linked trait and most of the reported patients were hemizygous males. However, heterozygous females may have a variable degree of hemolytic anemia. All women born to affected men will be carriers (mild manifesting or not) with no male to male transmission. Female carriers have a 50 % risk of an affected male or female carrier with each pregnancy.
Management and treatment
In patients with severe chronic anemia, regular blood transfusions are required. Splenectomy has been shown to be beneficial in some cases.
The prognosis is variable, depending on the severity of the anemia and on the presence of the other manifestations.
- Guidance for genetic testing
- Français (2019, pdf)