eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Glycogen-Storage Disease Type VII

Lynne Ierardi-Curto, MD, PhD, Medical Geneticist, Laboratory Corporation of America (LabCorp), Northeast Division, Genetics Services

Updated: Feb 5, 2009

Introduction

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.

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.

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. 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, patients with Tarui disease who consume glucose prior to exercise experience what Haller and Lewis call the "out of wind" phenomenon.⁴ Some discrepancy surrounds the ability of patients with PFKD to develop a spontaneous second wind. Another study by Haller's group showed that none of their patients developed a spontaneous second wind.⁵

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.

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. 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.⁶

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.

Clinical

History

The usual presenting symptom in Tarui disease (glycogen-storage disease type VII) 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 phosphofructokinase (PFK) deficiency may cause jaundice.
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.
Cardiac dysfunction, arrhythmia and anginal chest pain may be symptoms of the late-onset type.⁶

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

The cause of Tarui disease is 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 Jews 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.⁷

Differential Diagnoses

Glycogen-Storage Disease Type V

Workup

Laboratory Studies

Serum creatine kinase (CK) values are usually increased in patients with Tarui disease (glycogen-storage disease type VII).
Lactic acid does 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 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 reveal small-motor potentials of short duration consistent with myopathic changes.
Echocardiography may reveal valvular thickening, and ECG may reveal an arrhythmia.
The ischemic forearm test is an important tool for the diagnosis of muscle disorders. The test examines 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.
- Increased lactate 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.
- Positive ischemic forearm test results may occur in patients with Tarui disease, Cori disease (glycogen-storage disease type III), and McArdle disease (glycogen-storage disease type V).
Demonstration of decreased phosphofructokinase (PFK) enzyme activity in muscle tissue by biochemical assay is considered definitive diagnosis of Tarui disease.

Procedures

Muscle biopsy is necessary for definitive diagnosis.

Histologic Findings

Glycogen accumulates between myofibrils under the sarcolemma, as in McArdle disease. Muscle glycogen content typically is 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 measured glycogen is typically greater than twice the normal amount.

Treatment

Medical Care

Specific medical treatment is not required for Tarui disease (glycogen-storage disease type VII). However, patients are advised 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

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

Follow-up

Further Outpatient Care

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 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.

Patient Education

As with all genetic diseases, genetic counseling is appropriate.

Miscellaneous

Medicolegal Pitfalls

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

References

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Keywords

glycogen-storage disease type VII, Tarui disease, Tarui's disease, muscle phosphofructokinase deficiency, phosphofructokinase deficiency, PFK, GSD type VII, glycogen storage disease type VII, type 7 glycogenosis, muscle weakness, psychomotor retardation, out of wind phenomenon, myoglobinuria, hemolysis, jaundice, gallstones, cholecystectomy, cardiomyopathy, respiratory failure, McArdle disease, gout, arthritis, blindness

Contributor Information and Disclosures

Author

Lynne Ierardi-Curto, MD, PhD, Medical Geneticist, Laboratory Corporation of America (LabCorp), Northeast Division, Genetics Services
Disclosure: Nothing to disclose.

Medical Editor

Edward Kaye, MD, Vice President of Clinical Research, Genzyme Corporation
Edward Kaye, MD is a member of the following medical societies: American Academy of Neurology, American Society of Gene Therapy, American Society of Human Genetics, Child Neurology Society, and Society for Inherited Metabolic Disorders
Disclosure: Genzyme Corporation Salary Management position

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Hagop Youssoufian, MD, MSc, Vice President of Clinical Research, ImClone Systems Incorporated
Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors Cydney L Fenton, MD, FAAP, and Melissa Wasserstein, MD, to the development and writing of this article.

Further Reading