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

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]}

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]

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.

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.

As with all genetic diseases, genetic counseling is appropriate.