Metabolic pathways of carbohydrates.
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:
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]
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 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.
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.
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.
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.
Obtain a creatine kinase level in all suspected cases of glycogen storage diseases (GSDs). Obtain urine studies because myoglobinuria may occur in some GSDs. Obtain fasting blood glucose because hypoglycemia may be found in some types of GSD.
Hepatic failure occurs 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. A biochemical assay of enzyme activity is necessary for definitive diagnosis.
Shen and colleagues demonstrated that DNA mutation analysis by polymerase chain reaction is effective for prenatal diagnosis.[14]
Akman and colleagues demonstrated that prenatal diagnosis of GSD IV by DNA analysis is accurate in genetically confirmed cases.[15]
Ischemic forearm test
An ischemic forearm test is an essential tool for diagnosing muscle disorders. The basic premise is an analysis of muscle activity's usual chemical reactions and products. 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 hold 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, at 5, 10, and 20 minutes.
Collect a final urine sample for myoglobin analysis.
With exercise, carbohydrate metabolic pathways yield lactate from pyruvate. Lack of lactate production during exercise indicates a pathway disturbance and suggests enzyme deficiency. In such cases, further evaluation is warranted with muscle biopsy with the biochemical assay.
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 is 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, McArdle, and Tarui disease.
Electromyography patterns are diverse and vary from patient to patient.
This study may reveal myopathic polyphasic response, but amplitude and duration may be decreased, as expected, or increased.
May also show spontaneous abnormal activity (fibrillation potential and positive sharp waves).
Myotonic discharges occur in some cases.
A prolonged QT interval may be present.
Twenty-two children with various GSD cases were identified and reviewed retrospectively, including nine with type VI disease. Liver biopsy demonstrated fibrosis, hepatocyte glycogenation, mild steatosis, lobular inflammatory activity, and periportal copper-binding protein staining.
Histopathological assessment of the liver involvement is superior to biochemical parameters. A liver biopsy may reveal chronic histological changes of varying severity despite a mild disease. All GSDs may manifest these findings on liver biopsy. Hence, definitive classification requires a mutational analysis.[16]
Unfortunately, no specific treatment or cure exists. The only way to yield the normal liver enzyme is by a liver transplant (LT). Hence, it is the only effective treatment in patients with liver failure. Matern and colleagues presented evidence that hepatic transplant may arrest GSD type IV effectively.[17] Ideally, patients should receive LT before developing an advanced disease, especially cardiomyopathy, as this can be fatal, and LT does not limit its progression. Combined liver and heart transplants may result in improved outcomes in such situations.[18] Ewert and colleagues reported successful heart transplantation in a patient with Andersen disease and cardiomyopathy.[19]
Dietary modifications to prevent the accumulation of abnormally formed glycogen have been considered as a possible treatment option to slow the progression of the disease and decrease clinical manifestations. A study aimed at exploring this theory was conducted in 15 patients with type IV GSD. Dietary modifications included maintaining a euglycemic state with a relatively high protein diet and carbohydrate restriction. Multidisciplinary monitoring of traditional markers of metabolic control, such as growth, serum aminotransferases, glucose homeostasis, lactate, and ketone levels, liver size and function, and symptoms and signs of portal hypertension was performed during this time. The study reported benefits in reducing symptoms and signs of the disease and prolonging survival. However, as mentioned above, an LT is the only treatment option for survival if there is a concern for progressive liver disease. Hence, evaluation for possible LT and dietary modifications should proceed in parallel, and LT should be performed without delay if there is a concern for advanced liver disease.[20]
Zingone and colleagues demonstrated the abolition of the murine clinical manifestations of von Gierke disease with a recombinant adenoviral vector.[21] 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.[22]
Supportive care is needed for individual manifestations, including liver failure, heart failure, and neurologic dysfunction. Consult a hepatologist regarding liver dysfunction and management, a cardiologist for heart dysfunction and management, and a neurologist versed in diagnosing and managing neuromuscular disorders.
Metabolic pathways of carbohydrates.
