Practice Essentials
A glycogen storage disease (GSD) results from an enzyme defect. These enzymes typically catalyze reactions that ultimately convert glycogen compounds to glucose; thus, an enzyme deficiency results in glycogen accumulation in specific tissues.
The following list contains a quick reference for 8 of the GSD types:
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0 - Glycogen synthase deficiency
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Ia - Glucose-6-phosphatase deficiency (von Gierke disease)
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II - Acid maltase deficiency (Pompe disease)
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III - Debranching enzyme deficiency (Forbes-Cori disease)
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IV - Transglucosidase deficiency (Andersen disease, amylopectinosis)
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V - Myophosphorylase deficiency (McArdle disease)
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VI - Phosphorylase deficiency (Hers disease)
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VII - Phosphofructokinase deficiency (Tarui disease)
Although at least 14 unique GSDs are discussed in the literature, the four 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). The von Gierke disease (GSD type Ia, glucose-6-phosphatase deficiency) causes clinically significant end-organ disease with substantial morbidity. The remaining GSDs are not benign but are less clinically significant; therefore, the physician should consider the GSDs above when initially entertaining the diagnosis of a GSD. Interestingly, GSD type 0, due to defective glycogen synthase, is also recognized.
GSD IV is an autosomal recessive metabolic disorder, with an incidence of 1 in 600,000 to 800,000. [1]
Signs and symptoms
Most patients experience muscle symptoms such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly. [2] Clinically, hepatosplenomegaly, cirrhosis of the liver, and hepatic failure are significant concerns.
Glycogen storage disease type IV (GSD IV), or Andersen disease, is an autosomal recessive disorder caused by mutations in the gene-encoding glycogen-branching enzyme necessary for normal glycogen metabolism. Decreased activity results in the accumulation of amylopectin-like polysaccharide (polyglucosan) in tissues, particularly the liver and muscle. [1, 3, 4]
The history is not specific for GSD IV. Patient complaints probably relate to end-organ injuries of Andersen disease, such as hepatic failure, cardiomyopathy, or muscular atrophy. Hypoglycemia is less common. Adults may present with central and peripheral nerve dysfunction. Sansone and colleagues report a distinct periodic paralysis of either hypokalemic or hyperkalemic type. [5, 6] Ventricular arrhythmia may occur.
Diagnosis
Diagnosis depends on the patient history and physical examination, muscle biopsy, electromyography, ischemic forearm test, and creatine kinase level. [7] Obtain a creatine kinase level in all cases of suspected GSD. Biochemical assay for enzyme activity is the method of definitive diagnosis. Glycogen structure shows fewer branching points and longer peripheral chains upon molecular analysis. Other GSDs do not have this abnormal glycogen structure. Fasting blood glucose testing is indicated because hypoglycemia sometimes can be found in some types of GSD. Urine studies may show myoglobinuria. Liver function studies may reveal evidence of hepatic injury.
Imaging may reveal hepatosplenomegaly, cardiomyopathy, or heart failure.
A liver biopsy may be needed to determine the cause of progressive liver dysfunction. Histologic findings are characteristic in the liver, with diffuse interstitial fibrosis, broad fibrous septa, and enlarged hepatocytes with periodic acid-Schiff positive inclusions. Electron microscopy shows alpha and beta glycogen particles.
Diffuse deposition of amylopectin-like materials in the heart, liver, muscle, spinal cord, and peripheral nerves may be present. Severe hepatic failure with possible malignant transformation results in death in childhood, usually by the second year.
See Workup for more detail.
Management
In general, no specific treatment exists to cure glycogen storage diseases (GSDs).
In some cases, diet therapy is helpful. Meticulous adherence to a dietary regimen to maintain a euglycemic state and prevent the formation of excessive glycogen may reduce the liver size, prevent hypoglycemia, reduce symptoms, and allow growth and development.
The only treatment option for an advanced hepatic disease is a liver transplant. Extrahepatic manifestations, including cardiomyopathy, cirrhosis, and neuromuscular dysfunction, require multidisciplinary management with a cardiologist, hepatologist, and neurologist.
See Treatment for more detail.
Pathophysiology
In type IV GSD the transglucosidase, an enzyme that is found in all tissues, is deficient. The condition is autosomal recessive. Due to abnormal glycogen, hepatic deposition may occur and can result in severe cirrhosis, hepatic failure, or neuromuscular failure. It can also present as abnormal liver function tests in its mildest presentation.
Cardiac and skeletal muscle may show PAS+ eosinophilic cytoplasmic inclusions.
Bruno and colleagues, Janecke et al, and others have demonstrated several novel mutations of the branching enzyme gene resulting in GSD type IV. [8, 9, 10, 11]
Lamperti et al noted a novel mutation in an infant who died at age 1 month from cardiorespiratory failure. [12] The branching enzyme gene sequence was found to contain a homozygous nonsense mutation, p.E152X, in exon 4, that correlated with a virtual absence of the branching enzyme biochemical activity in muscles and fibroblasts, as well as with a complete absence of such activity in the liver and heart.
The infant presented with symptoms consistent with congenital GSD type IV, including severe hypotonia, dilatative cardiomyopathy, mild hepatopathy, and brain lateral ventricle hemorrhage. [13] Muscle, heart, and liver specimens contained numerous vacuoles filled with PAS+ diastase-resistant materials, while electron microscopy revealed polyglucosan accumulations in all of the examined tissues. Polyglucosan was also found in vacuolated neurons.
Prognosis
Serious morbidities include hepatic failure, hepatosplenomegaly, and cardiomyopathy (less frequent). In general, GSDs present in childhood. Later onset correlates with a less severe form.
Liver failure may occur in the first 5 years of life due to deposition of glycogen.
Severe hepatic failure with possible malignant transformation results in death in childhood, usually by the second year.
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Metabolic pathways of carbohydrates.
