Genetics of Tarui Disease (Glycogen-Storage Disease Type VII or Phosphofructokinase Deficiency) 

Updated: May 21, 2018
Author: Renee J Chosed, PhD; Chief Editor: Maria Descartes, MD 

Overview

Background

In 1965, Tarui presented the first description of phosphofructokinase (PFK) deficiency in 3 adult siblings (born to consanguineous parents) with exercise intolerance and easy fatigability.[1] Increased muscle glycogen content and high levels of hexose monophosphates were noted. In vitro assays using patient muscle specimens revealed almost undetectable PFK enzyme activity, and patient blood samples exhibited erythrocyte PFK activity at about 50% of normal activity. Tarui disease (ie, glycogen-storage disease type VII) has since been described in more than 100 patients worldwide.[2]

Clinical history defines the 4 subtypes of Tarui disease, which include classic, infantile onset, late onset, and a hemolytic form. Symptoms of classic Tarui disease include exercise intolerance, fatigue, and myoglobinuria. Symptoms of infantile-onset Tarui disease may include hypotonia, myopathy, psychomotor retardation, cataracts, joint contractures, and death during childhood. Patients with late-onset Tarui disease may present in adulthood with progressive muscle weakness. Patients with the hemolytic form of Tarui disease do not present with muscle symptoms but rather exhibit nonspherocytic hemolytic anemia.[2, 3]

Pathophysiology

PFK is the key regulatory enzyme for glycolysis.[3] PFK catalyzes the irreversible transfer of phosphate from ATP to fructose-6-phosphate and converts it to fructose-1,6-bisphosphate during the third step in glycolysis. Thus, tissues deficient in PFK cannot utilize free or glycogen-derived glucose as a fuel source since the glycolytic pathway would be halted at this metabolic step. Glycogen accumulation can result as a consequence of impaired degradation or excess synthesis. In the case of PFK deficiency, glucose-6-phosphate accumulates owing to the blockage of the glycolytic flux, and this glycolytic metabolite activates glycogen synthetase (which catalyzes the conversion of glucose to glucose-1-phosphate during glycogenesis). Elevated levels of glucose 6-phosphate also activate the pentose phosphate pathway, leading to enhanced nucleotide formation and subsequent increased uric acid production and possible development of gout. The enzymatic block also causes a decrease in 2,3 bisphosphoglycerate (2,3 BPG), thus enhancing the affinity of hemoglobin for oxygen and increasing the formation of new erythrocytes, resulting in a compensated anemia.

There are three subunit isozymes of PFK in mammalian cells: muscle (M), liver (L), and platelet (P or C). Active PFK exists as a tetramer, and the composition of subunits differs according to the tissue type. Mature muscle expresses only the M isozyme; therefore, the muscle PFK is composed of homotetramers of M4. The liver and kidneys express predominately the L isoform. Erythrocytes express both M and L subunits, which randomly form tetramers of M4, L4, and the hybrid forms of the PFK enzyme.[4, 5]

In classic Tarui disease, the genetic defect involves the M isoform, resulting in the absence of PFK enzymatic activity in the muscle. Erythrocytes lack the M4 and hybrid isozymes and express only the L4 homotetramers, resulting in about 50% of normal PFK activity. Thus, hemolysis is a result of partial erythrocyte PFK deficiency. Because the liver and kidneys express only the L isoform, these organs are spared; however, the brain and heart express predominantly the M isoform, and their lack of clinical involvement in most reported cases of classic Tarui disease is not easily explained.[5]

In late-onset Tarui disease, the myopathic syndrome results from a mutation of the M subunit distinct from those that cause classic Tarui disease. In contrast to individuals with classic Tarui disease, who express only the L4 type isozyme in red blood cells, individuals with late-onset Tarui disease showed the presence of a few hybrid isozymes of M+L with the predominant L4 species, suggesting a "leaky" mutation of the gene coding the M subunit.[6]

Epidemiology

Frequency

International

Tarui disease is the least common glycogen-storage disease. Tarui disease is considered very rare, with more than 100 reported cases; however, because symptoms may be quite mild, the true incidence may be higher owing to a lack of recognition. Most of the reported cases are classic Tarui disease. Fatal infantile Tarui disease and the late-onset form are much rarer, with only several reported cases.

Mortality/Morbidity

Most patients with Tarui disease experience an early onset of fatigue and pain with exercise. The exercise intolerance is usually evident in childhood and worsens after moderate and intense exercise. Myoglobinuria and severe muscle cramps may follow vigorous exercise.

Carbohydrate-rich meals or glucose infusion prior to exercise typically exacerbates the exercise intolerance in patients with Tarui disease. This is in contrast to patients with McArdle disease, who report lessening of symptoms after eating a high-carbohydrate meal.[7] In an unaffected individual, active muscle is initially fueled by glucose derived from glycogen breakdown and then from blood-borne sources such as glucose and free fatty acids. However, patients with Tarui disease who consume glucose or sucrose prior to exercise exhibit a decrease in circulating free fatty acids and ketones that are normally used as alternative energy fuels ("out of wind" phenomenon).[8, 9, 10] The consumption of glucose signals the release of insulin from pancreatic beta-cells, leading to increased synthesis and subsequent storage of fatty acids as opposed to a release of this fuel source. In addition, the excess carbohydrates worsen the energy crisis in patients with Tarui disease because the metabolic block in PFK deficiency occurs below the entry of glucose into glycolysis, and, therefore, it cannot be used by the muscle for energy production.

Patients with Tarui disease do not exhibit the "second wind" phenomenon, characterized by a marked improvement in exercise tolerance and decreased heart rate after 6-8 minutes of aerobic exercise.[11] Instead, the "second wind" phenomenon is pathognomonic for McArdle disease (glycogen-storage disease type V).[12]

Patients with late-onset Tarui disease may have fixed muscle weakness. Myoglobinuria most likely develops following prolonged vigorous exercise. In rare instances, it progresses to renal failure. Hemolysis can cause jaundice, which may be severe.

Several patients have suffered from gallstones, requiring cholecystectomy. Elevated serum uric acid levels may cause clinical gout.

Portal and mesenteric vein thrombosis was reported in a 43-year-old man with known PFK deficiency.[13]

The initial description of the fatal infantile form of Tarui disease, a rare subtype, was of an infant with muscle weakness, seizures, cortical blindness, and corneal clouding who died of respiratory failure at age 7 months. Two siblings born to consanguineous Bedouin parents also had cardiomyopathy and died in infancy.[14] Other patients with the fatal infantile variant have had painful joint contractures. A preterm female infant born to nonconsanguineous parents exhibited hypotonia and floppy baby syndrome and was diagnosed with the infantile form of PFK deficiency. Analysis of a muscle biopsy sample showed excess glycogen and the absence of PFK activity. The infant died of respiratory failure at age 6 months. Interestingly, the authors noted glycogen accumulation in the cardiac muscle and hepatocytes of this patient.[15]

Mitral valve thickening and subsequent valve dysfunction, arrhythmia, and anginal chest pain was reported in one patient with late-onset Tarui disease.[16] Another patient with the late-onset form developed mild hypertrophic cardiomyopathy and paroxysmal atrial fibrillation.[5]

Sex

Tarui disease is inherited in an autosomal-recessive pattern. Males outnumber females in reported cases.

Age

Classic Tarui disease typically presents in childhood with exercise intolerance and anemia. The fatal infantile variant presents in the first year of life. All patients with reported cases died by age 4 years. The late-onset variant manifests during later adulthood with progressive limb weakness without myoglobinuria or cramps.

Prognosis

The small number of patients with the infantile variant have all died during early childhood.

The classic and late-onset types are relatively mild disorders with minor lifestyle restrictions.

Patient Education

As with all genetic diseases, genetic counseling is appropriate.

 

Presentation

History

The usual presenting symptoms of Tarui disease (glycogen-storage disease type VII) are exertional fatigue and muscle cramps. Most patients exhibit exertional fatigue in childhood and may experience nausea and vomiting, muscle cramps, hyperuricemia, myoglobinuria, or even anuria following high-intensity exercise. This constellation of signs and symptoms is characteristic not only of Tarui disease but a group of clinically and etiologically diverse conditions termed metabolic myopathies. The symptoms of exertional fatigue in patients with Tarui disease are typically more severe than those observed in McArdle disease (glycogen storage disease type V), the most common form of metabolic myopathy.

Hemolysis due to partial erythrocyte phosphofructokinase (PFK) deficiency may cause jaundice.

Myoglobinuria due to rhabdomyolysis has been reported.[7]

Hyperuricemia following exercise is due to accelerated degradation of muscle purine nucleotides, which serve as the substrates for the synthesis of uric acid. Manifestations of hyperuricemia may include arthritis.

Hypotonia, blindness, and psychomotor retardation may be the presenting symptoms of infantile-onset Tarui disease.

Cardiac dysfunction, arrhythmia, and anginal chest pain may be symptoms of late-onset Tarui disease.[16]

Physical

See the list below:

  • Classic and late-onset
    • Muscle weakness, most pronounced following exercise
    • Fixed limb weakness
    • Muscle contractures
    • Jaundice
    • Joint pain
  • Fatal infantile variant
    • Hypotonia, muscle weakness
    • Cataracts
    • Joint contractures

Causes

Tarui disease is genetic and is autosomal recessive.

Missense,[17, 18] splicing defects,[18, 19] , and frameshift mutations in the gene encoding the M subunit of PFK have been discovered in patients with Tarui disease. The M subunit gene, mapped to band 12p13, contains 24 exons and is approximately 30 kilobase (kb) in length.

Ashkenazi Jews share 2 common mutations in the PFKM gene. A splicing defect caused by the G-to-A base change at the first nucleotide in exon 5 accounts for 68% of mutant Ashkenazi alleles, and a deletion in exon 22 accounts for about 27% of mutant Ashkenazi alleles.[20]

Complications

Renal failure may complicate myoglobinuria.

Gallstones may complicate hyperbilirubinemia.

 

DDx

 

Workup

Laboratory Studies

Serum creatine kinase (CK) values are usually increased in patients with Tarui disease (glycogen-storage disease type VII).

Lactic acid levels do not increase following exercise.

Bilirubin levels may be elevated.

Reticulocyte count and reticulocyte distribution width (RDW) may be increased.

Urinalysis may reveal myoglobinuria, especially after exercise.

Imaging Studies

Brain imaging scans in patients with infantile-onset Tarui disease may show cortical atrophy and ventricular dilatation.

Phosphorus-31 nuclear magnetic resonance spectroscopy (31 P-NMR S) of calf muscle using a 4.7-Tesla MRI may be useful in diagnosis. During exercise, glycolytic intermediates accumulate as phosphorylated monoesters that are pathognomonic of Tarui disease. This study also shows the absence of lactic acid production.[21]

Other Tests

Electromyography 

Electromyography (EMG) may reveal small-motor potentials of short duration consistent with myopathic changes.

Echocardiography 

Echocardiography may reveal valvular thickening, and ECG may reveal an arrhythmia.

Ischemic forearm test 

The ischemic forearm test is an important tool for the diagnosis of metabolic myopathies. The test is used to examine the metabolic pathways that provide energy for muscle function during anaerobic exercise.

First, a blood pressure cuff is placed on the patient's arm and is inflated above systolic pressure.

The patient is then instructed to repetitively grasp an object (once or twice per second) for 2-3 minutes.

Blood samples for creatine kinase, ammonia, and lactate and urine samples for myoglobin analysis are immediately obtained before and 5 minutes, 10 minutes, and 20 minutes after inflating the cuff.

Healthy patients have an increase in lactate levels of at least 5-10 mg/dL and an increase in ammonia levels of at least 100 mcg/dL, with return to baseline. If neither level increases, the exercise was not strenuous enough, and the test results are not valid.

An increased lactate level at rest (before exercise) is evidence of mitochondrial myopathy.

Failure of ammonia to increase with lactate is evidence of myoadenylate deaminase deficiency. The failure of lactate to increase with ammonia is evidence of a glycogen-storage disease that results in blockage of a carbohydrate metabolic pathway.

Ischemic forearm test results may be positive in patients with Tarui disease, Cori disease (glycogen-storage disease type III), and McArdle disease (glycogen-storage disease type V).

Exercise test

The absence of a spontaneous second wind in a patient with suspected Tarui disease can be studied with an exercise test after an overnight fast. Continuous cycling for 15-20 minutes on a bicycle ergometer is maintained at a constant workload. Peak exercise capacity is determined after 6-8 minutes of exercise and again at 25-30 minutes of exercise. Heart rate is monitored continuously, and perceived exertion (Borg scale) is recorded during each minute of exercise. A spontaneous second wind is accompanied by decreased heart rate, perceived exertion, and increased oxygen consumption. Only patients with McArdle disease (glycogen-storage disease type V) exhibit a spontaneous second wind. A spontaneous second wind does not occur in patients with Tarui disease (glycogen-storage disease type VII), phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, and certain mitochondrial disorders.[22]

Glucose or sucrose intake before exercise will exacerbate the muscle symptoms in patients with Tarui disease. Thirty minutes before an exercise test, a beverage containing 75 grams of sucrose is ingested or a glucose infusion of 6 ml per minute is begun. Carbohydrate intake increases the symptoms of exercise intolerance in Tarui disease. In contrast, carbohydrate decreases the symptoms of exercise intolerance in McArdle disease (glycogen-storage disease type V) and has no effect on phosphoglycerate mutase deficiency[22] .

Muscle biopsy

Muscle biopsy may reveal elevated glycogen content. Demonstration of decreased phosphofructokinase (PFK) enzyme activity in muscle tissue is considered definitive biochemical diagnosis of Tarui disease.

Genetic analysis

The demonstration of homozygous or compound heterozygous mutations in the PFKM gene by sequence analysis is considered definitive molecular diagnosis of Tarui disease. Targeted mutation analysis may be considered in Ashkenazi Jewish patients and when a familial mutation has been identified.

Procedures

Muscle biopsy is necessary for microscopic and biochemical assay of PFK activity.

Histologic Findings

Glycogen accumulates between myofibrils under the sarcolemma, as in McArdle disease. Muscle glycogen content is typically greater than 1.5 g per 100 g wet muscle weight.

An abnormal polysaccharide, unique to Tarui disease, may also be found, especially in older patients. This polysaccharide is periodic acid-Schiff (PAS) positive but is not digested by diastase.

Nonspecific myopathic changes may also be observed.

In infantile-onset Tarui disease, little histological evidence of glycogen accumulation may be evident, but glycogen levels are typically more than twice the reference range.

 

Treatment

Medical Care

Specific medical treatment is not required for Tarui disease (glycogen-storage disease type VII). However, patients are advised to avoid sucrose and high-carbohydrate meals because they may exacerbate the exercise intolerance.

Activity

Instruct patients with Tarui disease to avoid vigorous exercise because it may lead to myoglobinuria.

Prevention

Prenatal detection is possible in families with identifiable mutations.

Long-Term Monitoring

Monitor renal function on a regular basis if a patient with Tarui disease (glycogen-storage disease type VII) has myoglobinuria.

Monitor hemoglobin and reticulocyte counts.

If the patient has hyperbilirubinemia, perform ultrasonography to evaluate for gallstones.

 

Medication

Medication Summary

Drug therapy is not currently a component of the standard of care for Tarui disease (glycogen-storage disease type VII).