AUTHOR INFORMATION

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Authored by Cydney L Fenton, MD, FAAP, Consulting Staff, Department of Pediatric Endocrinology, Children's Hospital Medical Center of Akron

Coauthored by Melissa Wasserstein, MD, Assistant Professor, Departments of Human Genetics and Pediatrics, Mount Sinai School of Medicine

Cydney L Fenton, MD, FAAP, is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society

Edited by Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MSc, MD, Medical Director, Adjunct Associate Professor, Clinical Discovery Department, Bristol-Myers Squibb; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Cydney L Fenton, MD, FAAP
Editor's Email:	Edward Kaye, MD

eMedicine Journal, March 29 2006, VOLUME 7, Number 3

INTRODUCTION

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Background: In 1965, Tarui presented the first description of phosphofructokinase (PFK) deficiency in 3 adult siblings with exercise intolerance and easy fatigability. 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 over 40 patients worldwide. 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 also is 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.

Pathophysiology: PFK catalyzes the irreversible conversion of fructose-6-phosphate to fructose-1, 6-bisphosphate in glycolysis; 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). 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, and, therefore, have 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 but 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 classic Tarui disease is not easily explained.

Frequency:

• Internationally: Tarui Disease is the least common type of glycogen storage disease. Tarui disease is rare, with approximately 40 reported cases; however, because symptoms may be quite mild, the true incidence may be higher due to lack of recognition. The fatal infantile variety is much rarer, with fewer than 10 reported cases. The late-onset form is the rarest, with fewer than 5 cases reported.

Mortality/Morbidity:

• Muscular weakness: Most patients experience an early onset of fatigue and pain with exercise. The exercise intolerance usually is 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. This is because active muscle initially is fueled on glucose derived from glycogen breakdown, which then derives its energy from blood-borne sources such as glucose and free fatty acids. As glucose causes a reduction in circulating levels of free fatty acids, Tarui patients who consume glucose prior to exercise experience what Haller and Lewis call the out of wind phenomenon.
    
    
  • Some discrepancy exists in the literature about the ability of patients with PFKD to develop a spontaneous second wind. A recent study by Haller's group showed that none of their patients developed a spontaneous second with.
    
    
  • 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.
  
  
• Fatal infantile form: The initial description of this rare subtype of Tarui disease 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. Other patients with the fatal infantile variant have had painful joint contractures.

Sex:

• Tarui disease is inherited in an autosomal recessive pattern. Tarui disease has a strong male predominance.

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.

CLINICAL

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History:

• The usual presenting symptom is exertional fatigue. Most patients exhibit exertional fatigue in childhood and may experience nausea and vomiting, muscle cramps, hyperuricemia, myoglobinuria, or even frank anuria following exercise. These symptoms are similar to, but more severe than, those observed in McArdle disease.



• Hemolysis due to partial erythrocyte PFK deficiency may cause jaundice.



• Gout: 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.



• Blindness and psychomotor retardation may be the presenting symptoms of the infantile-onset type.

Physical:

• Classic and late-onset


• • Muscle weakness, most pronounced following exercise
  
  
  
  • Fixed limb weakness
  
  
  
  • Muscle contractures
  
  
  
  • Jaundice
  
  
  
  • Joint pain
  
  
  
• Fatal infantile variant


• • Muscle weakness
  
  
  
  • Cataracts
  
  
  
  • Joint contractures
  
  
  

Causes:

• Genetic


• • Missense, splicing defects, 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 patients share 2 common mutations in the 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.
  
  
  

DIFFERENTIALS

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Glycogen-Storage Disease Type V

WORKUP

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Lab Studies:

• Serum creatine kinase (CK) values usually are increased.



• Lactic acid does not increase following exercise.



• Bilirubin may be elevated.



• Reticulocytosis may be increased.

Imaging Studies:

• Brain imaging scans in patients with the infantile-onset subtype may show cortical atrophy and ventricular dilatation.



• Phosphorus 31-nuclear magnetic resonance spectroscopy (31P-NMR S) of calf muscle using a 4.7 Tesla MRI may be useful in making this 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.

Other Tests:

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

TREATMENT

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Medical Care:

• Essentially, no treatment for this disorder exists. Instruct the patient to avoid high-carbohydrate meals because they may exacerbate the exercise intolerance.

Activity:

• Instruct the patient to avoid vigorous exercise because it may lead to myoglobinuria.

MEDICATION

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Drug therapy currently is not a component of the standard of care for this disease.

FOLLOW-UP

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Further Outpatient Care:

• Monitor renal function on a regular basis if the patient has myoglobinuria.



• Monitor hemoglobin and reticulocyte counts as well.



• If the patient has hyperbilirubinemia, perform ultrasonography to evaluate the presence of gallstones.

Deterrence/Prevention:

• Prenatal detection is possible in families with identifiable mutations.

Complications:

• Renal failure may complicate myoglobinuria.



• Gallstones may complicate hyperbilirubinemia.

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.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to limit exercise in a patient with myoglobinuria may lead to renal failure.

TEST QUESTIONS

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CME Question 1: Which of the following is not a typical feature of classic Tarui disease?

A: Exertional fatigue
B: Hypoglycemia
C: Myoglobinuria
D: Compensated hemolysis
E: Jaundice

The correct answer is B: Classic Tarui disease is caused by a deficiency of the M-subunit of phosphofructokinase. This subunit is expressed in the muscle, erythrocyte, brain, and heart, causing the classic findings of exercise intolerance with myoglobinuria and compensated anemia with jaundice. Because the M-subunit is not expressed in the liver, hypoglycemia is not part of the clinical spectrum.

CME Question 2: Which of the following laboratory findings in a patient who is myopathic strongly suggests Tarui disease?

A: Elevated lactate-to-pyruvate ratio
B: Increased lactate
C: Failure of serum lactate to increase following exercise
D: Low creatine kinase (CK)
E: None of the above

The correct answer is C: Phosphofructokinase (PFK) is an enzymatic intermediate in the glycolytic pathway; thus, production of the end product of glycolysis, pyruvate, is impaired in PFK deficiency. Lactate is produced from pyruvate under anaerobic conditions, and, therefore, fails to increase after exercise in PFK deficiency. Elevated lactate and abnormal lactate-to-pyruvate ratios in a myopathic patient are more suggestive of mitochondrial disease. CK is elevated in Tarui disease.

Pearl Question 1 (T/F): The typical clinical presentation in a patient with Tarui disease is exercise intolerance.

The correct answer is True: Fatigue and muscle cramping follows exercise. Some patients may have dark urine due to myoglobinuria. Muscular weakness also may be present.

Pearl Question 2 (T/F): The histological finding on a muscle biopsy in patients with Tarui disease is glycogen deposits.

The correct answer is True: Glycogen deposits accumulate between the myofibrils. A unique form of glycogen that is periodic acid-Schiff positive but not digested by diastase also is observed often, especially in older patients.

Pearl Question 3 (T/F): The hematological abnormality associated with Tarui disease is neutropenia.

The correct answer is False: A compensated hemolytic anemia is the hematological abnormality associated with Tarui disease. The anemia is caused by deficient phosphofructokinase activity in the erythrocyte. It is compensated because the enzymatic block leads to an elevated 2,3 diphosphoglycerate (DPG), which stimulates reticulocyte formation.

Pearl Question 4 (T/F): Tarui disease is inherited in an autosomal dominant fashion.

The correct answer is False: Tarui disease is an autosomal recessive disorder. Assuming that both parents are carriers of the disease, each child has a 1 in 4 chance of being affected.

BIBLIOGRAPHY

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• Amit R, Bashan N, Abarbanel JM, et al: Fatal familial infantile glycogen storage disease: multisystem phosphofructokinase deficiency. Muscle Nerve 1992; 14: 455-458[Medline].
• Chen YT, Burchell A: Glycogen Storage Diseases. In: The Metabolic and Molecular Bases of Inherited Disease. 1995: 954-5.
• Danon MJ, Carpenter S, Manaligod JR, Schliselfeld LH: Fatal infantile glycogen storage disease: deficiency of phosphofructokinase and phosphorylase b kinase. Neurology 1981; 31: 1303[Medline].
• Danon MJ, Servidei S, DiMauro S, Vora S: Late-onset muscle phosphofructokinase deficiency. Neurology 1988 Jun; 38(6): 956-60[Medline].
• DiMauro S, Tsujino S: Nonlysosomal glycogenoses. In: Myology: Basic and Clinical, 2nd ed. 1994: 1563-7.
• Dunaway GA: A review of animal phosphofructokinase isozymes with an emphasis on their physiological role. Mol Cell Biochem 1983; 52(1): 75-91[Medline].
• Dunaway GA, Kasten TP, Sebo T, Trapp R: Analysis of the phosphofructokinase subunits and isoenzymes in human tissues. Biochem J 1988 May 1; 251(3): 677-83[Medline].
• Exantus J, Ranchin B, Dubourg L, et al: Acute renal failure in a patient with phosphofructokinase deficiency. Pediatr Nephrol 2004 Jan; 19(1): 111-3[Medline].
• Finsterer J, Stollberger C, Kopsa W: Neurologic and cardiac progression of glycogenosis type VII over an eight-year period. South Med J 2002 Dec; 95(12): 1436-40[Medline].
• Guibaud P, Carrier H, Mathieu M, et al: [Familial congenital muscular dystrophy caused by phosphofructokinase deficiency]. Arch Fr Pediatr 1978 Dec; 35(10): 1105-15[Medline].
• Haller RG, Lewis SF: Glucose-induced exertional fatigue in muscle phosphofructokinase deficiency. N Engl J Med 1991 Feb 7; 324(6): 364-9[Medline].
• Haller RG, Vissing J: No spontaneous second wind in muscle phosphofructokinase deficiency. Neurology 2004 Jan 13; 62(1): 82-6[Medline].
• Hays AP, Hallett M, Delfs J, et al: Muscle phosphofructokinase deficiency: abnormal polysaccharide in a case of late-onset myopathy. Neurology 1981 Sep; 31(9): 1077-86[Medline].
• Mineo I, Kono N, Hara N, et al: Myogenic hyperuricemia. A common pathophysiologic feature of glycogenosis types III, V, and VII. N Engl J Med 1987 Jul 9; 317(2): 75-80[Medline].
• Raben N, Sherman JB: Mutations in muscle phosphofructokinase gene. Hum Mutat 1995; 6(1): 1-6[Medline].
• Rowland LP, DiMauro S, Layzer RB: Phosphofructokinase Deficiency. In: Myology. 1986: 1603-17.
• Servidei S, Bonilla E, Diedrich RG, et al: Fatal infantile form of muscle phosphofructokinase deficiency. Neurology 1986 Nov; 36(11): 1465-70[Medline].
• Tarui S, Okuno G, Ikura Y, et al: Phosphofructokinase deficiency in skeletal muscle: a new type of glycogenosis. Biochem Biophys Res Commun 1965 May 3; 19: 517-23[Medline].

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