INTRODUCTION — Glycogen is the stored form of glucose and serves as a buffer for glucose needs. It is composed of long polymers of a 1-4 linked glucose, interrupted by a 1-6 linked branch point every 4 to 10 residues. Glycogen is formed in periods of dietary carbohydrate loading and broken down when glucose demand is high or dietary availability is low (figure 1).
There are a number of inborn errors of glycogen metabolism that result from pathogenic variants in genes for virtually all of the proteins involved in glycogen synthesis, degradation, or regulation. Those disorders that result in abnormal storage of glycogen are known as glycogen storage diseases (GSDs). They have largely been categorized by number according to the chronology of recognition of the responsible enzyme defect (table 1). The age of onset varies from in utero to adulthood.
Glycogen is most abundant in liver and muscle, which are most affected by these disorders. The physiologic importance of a given enzyme in liver and muscle determines the clinical manifestations of the disease.
●The main role of glycogen in the liver is to store glucose for release to tissues that are unable to synthesize significant amounts during fasting. The major manifestations of disorders of glycogen metabolism affecting the liver are hypoglycemia and hepatomegaly. (See "Physiologic response to hypoglycemia in normal subjects and patients with diabetes mellitus".)
●Glycogen is the primary source of energy for high-intensity muscle activity by providing substrates for the generation of adenosine triphosphate (ATP). The major manifestations of disorders of glycogen metabolism affecting muscle are muscle cramps, exercise intolerance and easy fatigability, and progressive weakness.
This topic will review muscle phosphofructokinase (PFK) deficiency (GSD VII, MIM 232800), also known as Tarui disease. An overview of GSD is presented separately. (See "Overview of inherited disorders of glucose and glycogen metabolism".)
PHOSPHOFRUCTOKINASE — PFK is a glycolytic enzyme that catalyzes the conversion of fructose 6-phosphate to fructose 1,6-bisphosphate (figure 1). When PFK is deficient, the resulting block in glycolysis leads to a secondary glycogenosis.
PFK is a tetrameric enzyme composed of three distinct subunits: L (liver), M (muscle), and P (platelet). Expression of the subunits is tissue specific. The enzyme in erythrocytes is a 50:50 hybrid of the M and L types . The vast majority of patients with GSD VII lack the muscle-specific isoform of PFK. Normal isoforms are present in platelets and liver.
GENETICS — Inheritance is autosomal recessive. The disorder is caused by pathogenic variants in the gene for the M (muscle) isoform of PFK, located at 12q13 . The genes for the L (liver) and P (platelet) subunits have been mapped to chromosomes 21 and 10, respectively . Partial deficiency of PFK activity (approximately 50 percent) is present in erythrocytes as a result of functional homotetramers of the normal liver subunit . Tissues that primarily express the non-M PFK subunits, such as platelets and liver, are not affected.
A variety of mutations have been described [5,6]. A founder mutation is present in the majority of Ashkenazi Jewish patients that alters a splice site, leading to exon skipping . This splice-site mutation and another single nucleotide deletion account for approximately 95 percent of the mutations responsible for muscle PFK deficiency in this population .
CLINICAL FEATURES — The disease typically presents in childhood with fatigue, muscle cramps, and exercise intolerance [9,10]. A high-carbohydrate meal or administration of glucose prior to exercise aggravates symptoms due to decreased availability of free fatty acids and ketones . Patients with PFK deficiency do not develop a spontaneous second wind under conditions that produce one in patients with McArdle disease (muscle phosphorylase deficiency) . This seems to be related to the inability of PFK-deficient muscle to metabolize glucose.
Patients often have exertional rhabdomyolysis with myoglobinuria. Some have erythrocyte hemolysis, a feature of several disorders of glycolysis. This usually is compensated by increased red blood cell production. "Myogenic hyperuricemia" and gout may be seen and can occur in the absence of clinically apparent skeletal muscle involvement [13,14].
Presentation sometimes occurs in middle age to late adulthood with fixed muscle weakness and progressive atrophy [15,16]. As an example, a 41-year-old patient presented with slowly progressive muscle weakness since childhood, without episodes of rhabdomyolysis or hemolytic anemia . There are case reports of infants with apparent deficiency of all three isoforms of phosphofructokinase, associated with central nervous system disease, skeletal myopathy, and cardiomyopathy . Infantile cases presenting with neonatal epilepsy, arthrogryposis multiplex congenita, or corneal opacifications have also been described [19-21], but none had evidence of hemolytic anemia. Considering the rarity of GSD VII and the even more rare severe infantile-onset disease, it is possible that children with the severe phenotype have a second genetic condition accounting for the central nervous system (CNS) symptoms (molecular double trouble) . One adult patient with a long history of muscle cramps and exercise intolerance but no fixed muscle weakness showed a mild hypertrophic cardiomyopathy with atrial fibrillation . The mechanism that accounts for multisystem disease is unknown but may be due to absence of an activator that is common to all the isoforms.
DIAGNOSIS — Serum creatine kinase concentration is usually elevated. Red blood cell PFK activity is typically reduced to approximately one-half of normal. A mild hemolytic anemia may be present, sometimes with mild hyperbilirubinemia; although anemia is rare, reticulocytosis is common. Patients often have hyperuricemia due to increased degradation of purine nucleotides in muscle [13,14]. The ischemic forearm exercise test shows no rise in lactate levels, but ergometric exercising demonstrates a late rise in lactate that may result from shunting of glucose 6-phosphate through the pentose phosphate pathway, a feature not observed in myophosphorylase deficiency (GSD V, McArdle disease) .
Muscle biopsy reveals a modest increase in subsarcolemmal glycogen that has a normal appearance . In older patients, an abnormal polysaccharide with a filamentous fine structure resembling that of glycogen brancher enzyme deficiency may be present . PFK activity is deficient in muscle and is reduced by approximately 50 percent in erythrocytes.
Genetic diagnosis by sequencing analysis of the PFK muscle isoform (PFKM) gene is clinically available. Among patients of Ashkenazi Jewish ancestry, diagnosis through genetic testing for the two most common mutations in this population has been suggested .
TREATMENT — There is no specific treatment for this disorder. Patients should avoid strenuous exercise. Glucose intake prior to exercise is not useful, and, in fact, it may be detrimental due to reduction in the concentration of alternative fuels like fatty acids and ketones . In one patient with infantile onset, cardiomyopathy and strength improved with a ketogenic diet that was used to bypass the glycolytic block, although he subsequently died . In an adult with GSD VII, the implementation of a ketogenic diet as a modified Atkins diet over a five-year period led to an alleviation of muscle symptoms, beneficial effects on breathing, and improvement in exercise performance and oxygen uptake . Thus, a ketogenic diet administered under close nutritional and medical supervision is an option for selected patients.
SUMMARY AND RECOMMENDATIONS
●Enzyme function – Phosphofructokinase (PFK) is a glycolytic enzyme that catalyzes the conversion of fructose 6-phosphate to fructose 1,6-bisphosphate (figure 1). Deficiency of PFK results in secondary glycogenosis. (See 'Phosphofructokinase' above.)
●Genetics – PFK deficiency (also known as glycogen storage disease [GSD] VII and Tarui disease) has an autosomal-recessive inheritance pattern. It is caused by a variety of mutations in the gene for the M (muscle) isoform of PFK. (See 'Genetics' above.)
●Clinical features – PFK deficiency typically presents in childhood with fatigue, muscle cramps, and exercise intolerance (table 1). These symptoms may be exacerbated when exercise is preceded by a high-carbohydrate meal or administration of glucose. Additional findings may include exertional rhabdomyolysis with myoglobinuria, erythrocyte hemolysis, hyperuricemia, and gout. (See 'Clinical features' above.)
●Laboratory findings and diagnosis – Laboratory features suggestive of the diagnosis may include elevated serum creatine kinase, decreased red blood cell PFK activity (to approximately one-half of normal), mild hemolytic anemia, reticulocytosis, and hyperuricemia. The ischemic forearm exercise test shows no rise in lactate levels. The diagnosis is confirmed with muscle biopsy demonstrating deficient PFK activity or alternatively by detecting DNA mutations of known pathogenicity. (See 'Diagnosis' above.)
●Management – There is no specific treatment for the more common form of the disease. Patients should avoid strenuous exercise. (See 'Treatment' above.)