Genetics of Glycogen-Storage Disease Type VII

Updated: Oct 03, 2013
  • Author: Lynne Ierardi-Curto, MD, PhD; Chief Editor: Maria Descartes, MD  more...
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Overview

Background

In 1965, Tarui presented the first description of phosphofructokinase (PFK) deficiency in 3 adult siblings with exercise intolerance and easy fatigability. [1] Increased muscle glycogen content and high levels of hexose monophosphates were noted. Assays for muscle PFK revealed almost undetectable activity, and erythrocyte PFK had about 50% normal activity. Tarui disease (ie, glycogen-storage disease type VII) has since been described in approximately 100 patients worldwide. [2]

Clinical history defines the 3 subtypes, which are classic, infantile onset, and late onset. Symptoms of classic Tarui disease include exercise intolerance, fatigue, and myoglobinuria. A compensated hemolysis is also commonly present. Symptoms of the infantile form may include myopathy, psychomotor retardation, cataracts, joint contractures, and death during childhood. Patients with the late-onset form may present in adulthood with progressive muscle weakness.

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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. Thus, tissues deficient in PFK cannot use free or glycogen-derived glucose as a fuel source. Glycogen accumulation is a consequence of impaired degradation or excess synthesis. The hexose monophosphates, which accumulate because of the enzymatic block, activate glycogen synthetase. Although elevated levels of glucose 6-phosphate activate the hexose monophosphate shunt, nucleotide formation is enhanced, leading to increased uric acid production and possible development of gout. The enzymatic block also causes a decrease in 2,3 diphosphoglycerate (DPG), thus enhancing the oxygen affinity of hemoglobin and increasing the formation of new erythrocytes, resulting in a compensated anemia.

Mammalian PFK acts as a tetramer composed of 3 subunits, muscle (M), liver (L), and platelet (P). The composition of the PFK tetramer 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 tetramerize to form M4, L4, and the 3 hybrid forms of the enzyme.

In classic Tarui disease, the genetic defect involves the M isoform, resulting in the absence of enzymatic activity in the muscle. Erythrocytes lack the M4 and hybrid isozymes and only express 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.

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Epidemiology

Frequency

International

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

Mortality/Morbidity

Most patients 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. 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). [4, 5, 6]

In addition, the excess carbohydrate worsens the energy crisis in 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. [7] Instead, the "second wind" phenomenon is pathognomonic for McArdle disease (glycogen-storage disease type V). [8]

Patients with the late-onset form 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 a 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. [9]

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. [10] Other patients with the fatal infantile variant have had painful joint contractures.

Mitral valve thickening and subsequent valve dysfunction, arrhythmia, and anginal chest pain was reported in one patient with the late-onset form. [11] Another patient with the late-onset form developed mild hypertrophic cardiomyopathy and paroxysmal atrial fibrillation. [12]

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 of reported cases died by age 4 years. The late-onset variant manifests itself during later adulthood with progressive limb weakness without myoglobinuria or cramps.

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