Type IV Glycogen Storage Disease

Practice Essentials

Glycogen storage disease type IV (GSD IV), or Andersen disease, is an autosomal recessive inborn error of metabolism that is caused by mutations in the gene-encoding glycogen-branching enzyme, which is necessary for normal glycogen production. Decreased activity causes results in the accumulation of amylopectin-like polysaccharide (polyglucosan) in tissues, particularly liver and muscle.^{[1, 2, 3]} 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.^[4]  Clinically, hepatosplenomegaly, cirrhosis of the liver, and hepatic failure are major concerns.

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 rarely seen. 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 depends on patient history and physical examination, muscle biopsy, electromyelography, ischemic forearm test, and creatine kinase level.^[7]   Biochemical assay for enzyme activity is the method of definitive diagnosis. Obtain a creatine kinase level in all cases of suspected GSD. Because hypoglycemia may be found in some types of GSD, fasting glucose testing is indicated. Urine studies are indicated because myoglobinuria may occur in some GSDs. Liver function studies are indicated and may reveal evidence of hepatic injury. Glycogen structure is altered, with fewer branching points and longer peripheral chains. This abnormal glycogen structure is absent in other GSDs.

Imaging may reveal hepatosplenomegaly, cardiomyopathy, or heart failure.

Liver biopsy may be needed to determine the cause of progressive liver dysfunction. Histologic findings are characteristic in the liver, with diffuse interstitial fibrosis, wide 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.

Unfortunately, no specific treatment or cure exists, although diet therapy may be highly effective at reducing clinical manifestations. In some cases, liver transplantation may abolish biochemical abnormalities. Meticulous adherence to a dietary regimen may reduce liver size, prevent hypoglycemia, reduce symptoms, and allow for growth and development.

Severe hepatic failure with possible malignant transformation results in death in childhood, usually by the second year. Matern and colleagues present evidence that hepatic transplant may be effective at arresting GSD type IV.^[8]  

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, which is due to defective glycogen synthase, is also recognized.

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Pathophysiology

Transglucosidase, which is found in all tissues, is deficient. The condition is autosomal recessive. Due to abnormal glycogen, hepatic deposition may occur and result in severe cirrhosis, hepatic failure, or neuromuscular failure. It also can 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 IV.^{[9, 10, 11, 12]}

Lamperti et al noted a novel mutation in an infant who died at age 1 month of cardiorespiratory failure.^[13] 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 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 IV, including severe hypotonia, dilatative cardiomyopathy, mild hepatopathy, and brain lateral ventricle hemorrhage.^[14] 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.

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Epidemiology

GSD IV is an autosomal recessive metabolic disorder, with an incidence of 1 in 600,000 to 800,000.^[1]  

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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Laboratory Studies

Obtain a creatine kinase level in all cases of suspected glycogen storage diseases (GSDs).

Because hypoglycemia may be found in some types of GSD, fasting glucose testing is indicated.

Urine studies are indicated because myoglobinuria may occur in some GSDs.

Hepatic failure occurs in some GSDs. Liver function studies are indicated and may reveal evidence of hepatic injury.

Biochemical assay of enzyme activity is necessary for definitive diagnosis. Glycogen structure is altered, with fewer branching points and longer peripheral chains. This abnormal glycogen structure is absent in other GSDs.

Shen and colleagues demonstrated that DNA mutation analysis by polymerase chain reaction is effective for prenatal diagnosis.^[15]

Akman and colleagues demonstrated that prenatal diagnosis of GSD IV by DNA analysis is accurate in the genetically confirmed cases.^[16]

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Other Tests

Ischemic forearm test

The ischemic forearm test is an important tool for the 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.

Instruct the patient to rest. Position a loosened blood pressure cuff on the arm, and place a venous line for blood samples from 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.

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.

Failure of ammonia to increase with lactate is evidence of myoadenylate deaminase deficiency.

A positive ischemic forearm test may occur in Cori disease, McArdle disease, and Tarui disease.

Electromyelography

Electromyelography patterns are diverse and vary from patient to patient.

Myopathic polyphasic responses are found, but amplitude and duration may be either decreased, as expected, or increased.

Spontaneous abnormal activity (fibrillation potential and positive sharp waves) may be found.

Myotonic discharges occur in some cases.

Electrocardiography

A prolonged QT interval may be present.

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Medical Care

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 may reduce liver size, prevent hypoglycemia, reduce symptoms, and allow for growth and development.

Liver transplantation may be indicated for patients with classic and progressive hepatic disease.

Ewert and colleagues report successful heart transplantation in a patient with Andersen disease and cardiomyopathy.^[17]

Zingone and colleagues demonstrated the abolition of the murine clinical manifestations of von Gierke disease with a recombinant adenoviral vector.^[18] 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.^[19]

Supportive care is needed for individual manifestations, including liver failure, heart failure, and neurologic dysfunction.

Growing evidence indicates that a high-protein diet may provide increased muscle function in patients with weakness or exercise intolerance. Evidence also exists that a high-protein diet may slow or arrest disease progression.

Consult a hepatologist regarding liver dysfunction and management, a cardiologist for heart dysfunction and management, and a neurologist who is versed in the diagnosis and management of neuromuscular disorders.

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