|Genetics||Pathogenic variants in muscle isoform of PFK|
|Pathophysiology||Phosphofructokinase deficiency resulting in secondary glycogenosis|
Tarui Disease (also known as Glycogen Storage Disease Type VII) is an autosomal recessive disorder of carbohydrate metabolism characterised by the absence of phosphofructokinase. It belongs to the group of Glycogen Storage Diseases.
The disorder is inherited in an autosomal recessive manner, caused by pathogenic variations in the gene that codes for the M isoform (muscle) of PFK.
PFK is an enzyme involved in the process of glycolysis that converts fructose 6-phosphate to fructose 1,6-bisphosphate. When there is a deficiency of PFK, it leads to secondary glycogenosis.
Typically, the disease shows symptoms in childhood, including fatigue, muscle cramps, and exercise intolerance. Symptoms worsen after a high-carbohydrate meal or glucose administration before exercise due to a decrease in free fatty acids and ketones.
PFK-deficient muscles cannot metabolize glucose, which is thought to be why patients do not experience a second wind like those with McArdle disease. Exertional rhabdomyolysis with myoglobinuria is common, and some patients also experience erythrocyte hemolysis, which is compensated for by increased red blood cell production. Gout with myogenic hyperuricemia can occur even without apparent skeletal muscle involvement.
In some cases, patients present with progressive muscle weakness and atrophy in middle age or later adulthood. Severe infantile-onset cases have been reported, with symptoms such as central nervous system disease, skeletal myopathy, and cardiomyopathy. There may be a second genetic condition in these cases, as the mechanism behind multisystem disease is unclear but may be due to the absence of an activator common to all PFK isoforms.
The concentration of serum creatine kinase is usually high, and red blood cell PFK activity is usually reduced by about 50 percent. Patients may have mild hemolytic anemia and mild hyperbilirubinemia, although anemia is rare, but there may be an increase in reticulocytes. Patients often have hyperuricemia due to increased degradation of purine nucleotides in muscles. The ischemic forearm exercise test does not show an increase in lactate levels, but ergometric exercising demonstrates a late rise in lactate, which may be due to the shunting of glucose 6-phosphate through the pentose phosphate pathway.
Muscle biopsy reveals a slight increase in subsarcolemmal glycogen that has a normal appearance, while older patients may have an abnormal polysaccharide with a filamentous fine structure resembling that of glycogen brancher enzyme deficiency. PFK activity is deficient in muscles and reduced by about 50 percent in erythrocytes.
A genetic diagnosis can be made by sequencing analysis of the PFKM gene, and in patients of Ashkenazi Jewish ancestry, genetic testing for the two most common mutations in this population is recommended.
There is no specific treatment
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