Practice Essentials
A glycogen storage disease (GSD) is the result of an enzyme defect. These enzymes normally catalyze reactions that ultimately convert glycogen compounds to glucose. Enzyme deficiency results in glycogen accumulation in tissues. In many cases, the defect has systemic consequences, but in some cases, the defect is limited to specific tissues. Most patients experience muscle symptoms, such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly.
The diagram below illustrates metabolic pathways of carbohydrates.
View Image | Metabolic pathways of carbohydrates. |
The following list contains a quick reference for 8 of the GSD types:
0 - Glycogen synthase deficiency
Ia - Glucose-6-phosphatase deficiency (von Gierke disease)
II - Acid maltase deficiency (Pompe disease)
III - Debranching enzyme deficiency (Forbes-Cori disease)
IV - Transglucosidase deficiency (Andersen disease, amylopectinosis)
V - Myophosphorylase deficiency (McArdle disease)
VI - Phosphorylase deficiency (Hers disease)
VII - Phosphofructokinase deficiency (Tarui disease)
Although at least 14 unique GSDs are discussed in the literature, the 4 that cause clinically significant muscle weakness are Pompe disease (GSD type II, acid maltase deficiency), Cori disease (GSD type III, debranching enzyme deficiency), McArdle disease (GSD type V, myophosphorylase deficiency), and Tarui disease (GSD type VII, phosphofructokinase deficiency). One form, von Gierke disease (GSD type Ia, glucose-6-phosphatase deficiency), causes clinically significant end-organ disease with significant morbidity. The remaining GSDs are not benign but are less clinically significant; therefore, the physician should consider the aforementioned GSDs when initially entertaining the diagnosis of a GSD. Interestingly, GSD type 0 also is described and is a disorder causing glycogen deficiency due to defective glycogen synthase.
These inherited enzyme defects usually present in childhood, although some, such as McArdle disease and Pompe disease, have separate adult-onset forms. In general, GSDs are inherited as autosomal recessive conditions. Several different mutations have been reported for each disorder.[1]
Diagnosis
Diagnosis depends on findings from patient history and physical examination, creatine kinase testing, muscle biopsy, electromyelography, and ischemic forearm testing. Biochemical assay for enzyme activity is the method of definitive diagnosis.
Myophosphorylase, the deficient enzyme in McArdle disease, is found in muscle tissue. Myophosphorylase deficiency causes muscle cramps, pain, and stiffness. One hallmark of McArdle disease is weakness with exertion. Proximal muscle weakness may progress with time, and no specific treatment exists.
Management
Unfortunately, no specific treatment or cure exists for GSDs, although diet therapy may be highly effective at reducing clinical manifestations. In some cases, liver transplantation may abolish biochemical abnormalities. Active research continues.
Patient education
Genetic counseling is appropriate for all individuals with a genetic disorder.
Pathophysiology
The phenotype of the individual with GSD results from an enzyme defect. Carbohydrate metabolic pathways are blocked, leading to excess glycogen accumulation in affected tissues and/or disturbances in energy production. Several gene mutations have been described.[1]
Fatty acids and glucose serve as substrates for energy production. With intense exercise, glucose from glycogen stores in muscle becomes the predominant resource. Fatigue develops when the glycogen supply is exhausted.[2, 3] Each GSD represents a specific enzyme defect, and each enzyme is in specific, or most, body tissues. Myophosphorylase is found in muscle. Hypoglycemia is not an expected finding because liver phosphorylase is not involved.
GSD type V is an autosomal recessive disease resulting from mutations in the PYGM gene that encodes for the muscle isoform of glycogen phosphorylase (myophosphorylase). Heterozygotes usually do not manifest clinical features of the disease.[1]
Epidemiology
International statistics
Herling and colleagues studied the incidence and frequency of inherited metabolic conditions in British Columbia. GSDs are found in 2.3 children per 100,000 births per year. The prevalence of GSD type V is estimated to be around 1 in 100,000–140,000 persons. [1]
Age-related demographics
In general, GSDs present in childhood. Later onset correlates with a less severe form. Consider Pompe disease if onset is in infancy.
The majority of patients with McArdle disease present in the second to third decade of life.
Cheraud and colleagues report two unique cases of McArdle disease presenting in individuals in their seventies. Physicians should have clinical suspicion regardless of age of presentation.[4]
Prognosis
The life expectancy of patients with McArdle disease is typically not affected.[1] Pregnancy and childbirth outcomes are relatively unaffected by the disease.[5]
Morbidity/mortality
Immediate morbidity arises from severe exercise intolerance.
Complications
There are potential anesthetic and perioperative risks.[6]
History
Consider the following in the history:
Age at onset of symptoms depends on enzyme activity levels. Initial symptoms are cramps, fatigue, and pain after exercise.[7]
Because severity depends on enzyme activity, individual presentation is unique.
The rate of rise in oxygen consumption per unit time (VO2) is relative to work rate increases.
Some adults develop a progressive proximal weakness.
Some adults develop a fixed motor weakness.
The disorder has a unique "second-wind" phenomenon.[8] If a patient nearing fatigue slows exercise to a tolerable level, a point exists at which exercise may be increased again without previous symptoms[9] . According to Porcelli and colleagues, this phenomenon may be secondary to increased adrenergic response to exercise, influx of glucose, free fatty acids, and other substrates for muscle metabolism.[10]
Burgundy-colored urine is usually reported in patients but is not always present. It is thought to be a result of rhabdomyolysis after intense exercise.
Jones and colleagues report an unusual presentation of atypical chest pain and chronic troponinemia associated with hypertrophic cardiomyopathy among family members.[11]
Physical Examination
Physical examination is usually unremarkable in most patients. About 25% of patients may present with evidence of muscle hypertrophy. Proximal muscle wasting and weakness may be seen older patients.[5]
Consider the following in the physical examination:
Diagnosis is suggested by patient history.
Clinical findings may be absent upon physical examination.
Muscle strength and reflexes may be normal.
In later adult life, persistent weakness and muscle wasting may be present.
When clinical suspicion is present, diagnostic testing includes the ischemic forearm test, laboratory analysis, and electromyography.
About 10% of patients with GSD V may present with acute renal failure.[5]
Laboratory Studies
Obtain a creatine kinase level in all cases of suspected GSD. Creatine kinase levels are elevated in more than 90% of patients with McArdle disease. Bruno and colleagues report a case of elevated creatine kinase on routine screening as the only sign of McArdle disease in a 13-year-old boy.[12]
Because hypoglycemia may be found in some types of GSD, fasting glucose testing is indicated. Hypoglycemia is of concern and may lead to hypoglycemic seizures.
Urine studies are indicated because myoglobinuria may occur in some patients with GSDs.
Hepatic failure occurs in some patients with GSDs. Liver function studies are indicated. In general, the liver contains little myophosphorylase.
Myoglobinuria is found in 50% of patients after exercise.
Biochemical assay is required for definitive diagnosis. Phosphorylase reaction is absent.
Other Tests
Ischemic forearm test
The ischemic forearm test is an important tool for diagnosis of muscle disorders. The basic premise is an analysis of the normal chemical reactions and products of muscle activity. Obtain consent before the test.
First instruct the patient to rest. Position a loosened blood pressure cuff on the arm, and place a venous line for blood samples in the antecubital vein.
Obtain blood samples for the following tests: creatine kinase, ammonia, and lactate. Repeat in 5-10 minutes.
Obtain a urine sample for myoglobin analysis.
Immediately inflate the blood pressure cuff above systolic blood pressure and have the patient repetitively grasp an object, such as a dynamometer. Instruct the patient to grasp the object firmly, once or twice per second. Encourage the patient for 2-3 minutes, at which time the patient may no longer be able to participate. Immediately release and remove the blood pressure cuff.
Obtain blood samples for creatine kinase, ammonia, and lactate immediately and at 5, 10, and 20 minutes.
Collect a final urine sample for myoglobin analysis.
Interpretation of ischemic forearm test results
With exercise, carbohydrate metabolic pathways yield lactate from pyruvate. Lack of lactate production during exercise is evidence of a pathway disturbance, and an enzyme deficiency is suggested. In such cases, muscle biopsy with biochemical assay is indicated.
Healthy patients demonstrate an increase in lactate of at least 5-10 mg/dL and ammonia of at least 100 mcg/dL. Levels will return to baseline after the exercise is stopped.
If neither level increases, the exercise was not strenuous enough and the test is not valid.
Increased lactate at rest (before exercise) is evidence of mitochondrial myopathy.
Failure of lactate to increase with ammonia is evidence of a GSD resulting in a block in carbohydrate metabolic pathways. Not all patients with GSDs have a positive ischemic test result.
Failure of ammonia to increase with lactate is evidence of myoadenylate deaminase deficiency.
If a patient has McArdle disease, the ischemic forearm test results are positive.
Electromyography
In contrast to most GSDs, findings upon electromyography may be normal.
Findings from electromyography of resting muscle are normal.
Electrical activity is absent during contracture.
Repetitive nerve stimulation at low frequency (2 Hz) does not demonstrate an abnormal response, although repetitive stimulation at high frequency (15 Hz) may produce a decrement with contracture formation.
Single-fiber electromyography may reveal increased jitter.
Procedures
Muscle biopsy is necessary for assay of muscle enzyme activity.
Muscle biopsy findings may reveal fiber size variability, positive subsarcolemmal blebs with periodic acid-Schiff stain, and intermyofibril vacuoles. Felice and colleagues reported selective atrophy of type 1 muscle fibers.[13]
Medical Care
In general, no specific treatment exists for GSDs.
In some cases, diet therapy is helpful. Meticulous adherence to a dietary regimen may reduce liver size, prevent hypoglycemia, help with reduction in symptoms, and allow for growth and development. A high-protein diet may increase exercise tolerance in some cases, although this practice is controversial.[14]
Zingone and colleagues demonstrated the abolition of the murine clinical manifestations of von Gierke disease with a recombinant adenoviral vector.[15] These findings suggest that corrective gene therapy for GSDs may be possible in humans.
An encouraging study by Bijvoet and colleagues provides evidence of successful enzyme replacement for the mouse model of Pompe disease, which may lead to therapies for other enzyme deficiencies.[16]
Interest in glucagon treatment for McArdle disease has developed, but a study by Day and Mastaglia showed no benefit over placebo.[17]
Diet and Activity
Diet
A high-protein diet may increase exercise tolerance in some cases, although this practice is controversial.
Activity
Avoidance of intense physical activity usually ameliorates symptoms.
Author
Isaac Omolade Ogunmola, MBBS, Resident Physician, Department of Internal Medicine, Einstein Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
Catherine Anastasopoulou, MD, PhD, FACE, Associate Professor of Medicine, The Steven, Daniel and Douglas Altman Chair of Endocrinology, Sidney Kimmel Medical College of Thomas Jefferson University; Einstein Endocrine Associates, Einstein Medical Center
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Kent Wehmeier, MD, Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine
Disclosure: Nothing to disclose.
Chief Editor
George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
David M Klachko, MD, MEd, Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Missouri-Columbia School of Medicine
Disclosure: Nothing to disclose.
Wayne E Anderson, DO, FAHS, FAAN, Assistant Professor of Internal Medicine/Neurology, College of Osteopathic Medicine of the Pacific Western University of Health Sciences; Clinical Faculty in Family Medicine, Touro University College of Osteopathic Medicine; Clinical Instructor, Departments of Neurology and Pain Management, California Pacific Medical Center
Disclosure: Nothing to disclose.
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