eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Glycogen-Storage Disease Type IV
Updated: Apr 27, 2009
Introduction
Background
The classic presentation of glycogen-storage disease type IV (GSD IV), also known as Andersen disease, includes hepatosplenomegaly and failure to thrive during the first year of life, followed by progressive liver cirrhosis with portal hypertension and death, usually by age 5 years. The disorder is characterized by the appearance of abnormal, relatively insoluble glycogen with long, unbranched outer chains that result from defective glycogen-branching enzyme activity. Glycogen-storage disease type IV is actually a clinically heterogeneous disorder in which the age of onset, specific organ involvement, severity of symptoms, and degree of accumulation of abnormal glycogen in different tissues vary. Hypoglycemia is not a common feature in glycogen-storage disease type IV.
Progressive liver cirrhosis characterizes the classic form of glycogen-storage disease type IV. Patients with nonprogressive liver disease and later onset have a milder variant of the disease. In addition to these hepatic forms, 4 neuromuscular forms of glycogen-storage disease type IV have recently been identified. The congenital neuromuscular form and childhood neuromuscular form are associated with isolated or predominant muscle involvement, with the development of myopathy or cardiomyopathy at birth or during childhood, respectively. The perinatal form is distinguished by severe neuromuscular involvement and death. Finally, a subset of patients with clinically diagnosed adult polyglucosan body disease (APBD) have deficient glycogen-branching enzyme activity and diffuse CNS and peripheral nervous system dysfunction.
Pathophysiology
Deficient glycogen-branching enzyme activity results in the formation of abnormal glycogen with long, unbranched outer chains and decreased solubility. Although the glycogen concentration in tissue is usually not increased, the presence of insoluble glycogen can induce foreign-body reactions and lead to cellular injury and organ dysfunction. Patients with progressive liver disease ultimately develop cirrhosis and end-stage liver failure. Most of these patients develop portal hypertension and the following associated complications of portosystemic blood shunting:
- Esophageal varices
- Encephalopathy
- Splenomegaly
- Ascites
- Renal dysfunction
- Decreased albumin synthesis
- Decreased vitamin K–dependent coagulation factors
- Decreased fibrinogen level
- Decreased urea level
- Decreased clearance of drugs, bilirubin, bile acids, and waste nitrogen
- Abnormal steroid metabolism
- Impaired blood glucose maintenance
Abnormal glycogen in skeletal muscles may cause weakness, exercise intolerance, and muscle atrophy. Patients with cardiac involvement develop dilated cardiomyopathy and symptoms of progressive heart failure. In the nervous system, abnormal glycogen may lead to impaired cognition and both neuromuscular and neurovisceral dysfunction.
Frequency
International
Glycogen-storage disease type IV represents an uncommon form of glycogen-storage disease. The frequency of all forms of glycogen-storage disease is 1 case in 20,000-25,000 persons; glycogen-storage disease type IV accounts for approximately 3% of all cases.
Mortality/Morbidity
Classic glycogen-storage disease type IV causes progressive liver cirrhosis and death in children by age 5 years unless liver transplantation is performed. The perinatal form of the disease is invariably fatal. Patients with cardiomyopathy often develop progressive heart failure, which may lead to death despite medical and surgical intervention.
Patients with nonprogressive liver disease usually retain some hepatic function and do not require liver transplantation. An increased risk of hepatocellular adenoma and one case of hepatocellular carcinoma has been reported.
Neuromuscular dysfunction, although not life threatening, may be progressive and debilitating.
Race
A subgroup of patients, primarily people of Ashkenazi Jewish descent, have clinically diagnosed polyglucosan body disease and decreased glycogen-branching enzyme activity.
Sex
Both sexes are equally affected because the deficiency of glycogen-branching enzyme activity is inherited as an autosomal-recessive trait.
Age
In its classic form, glycogen-storage disease type IV presents during the first year of life with hepatosplenomegaly and failure to thrive. Patients with nonprogressive liver disease may present later in childhood. The perinatal form of glycogen-storage disease type IV presents in utero or immediately after birth. The age of onset in individuals with glycogen-storage disease type IV variants that predominantly feature nerve, muscle, or cardiac involvement ranges from early infancy through adulthood.
Clinical
History
- The classic presentation of glycogen-storage disease type IV (GSD IV) involves development of hepatosplenomegaly and failure to thrive in the first year of life.
- Patients with progressive liver cirrhosis and associated portal hypertension may also present with the following:
- Pruritus
- Fatigue
- Anorexia
- Weakness
- Jaundice
- Peripheral edema
- Epistaxis
- Easy bruising and bleeding
- Hepatic encephalopathy may cause lethargy, disorientation, or coma. Patients may present with hematemesis due to bleeding esophageal varices.
- Patients who are mildly affected with nonprogressive liver disease or early liver cirrhosis may be asymptomatic.
- The perinatal form of glycogen-storage disease type IV may include a history of fetal hydrops, cervical cystic hygroma, decreased in utero fetal movements, and severe hypotonia and cardiomyopathy at birth, leading to death in the neonatal period.1
- A milder congenital variant is associated with isolated hypotonia and gross motor delay, without hepatic or cardiac involvement.
- Patients with muscle involvement may present with muscle weakness, fatigue, and muscle atrophy.
- Patients with glycogen-storage disease type IV whose conditions involve associated dilated cardiomyopathy may present with the following:
- Failure to thrive
- Fatigue
- Irritability
- Anorexia and feeding problems
- Diaphoresis
- Dyspnea
- Orthopnea
- Edema
- Patients with central and peripheral nerve involvement (eg, adult polyglucosan body disease [APBD]) may present with the following:
- Muscle weakness
- Fatigue
- Gait disturbances
- Voiding difficulties (eg, neurogenic bladder)
- Peripheral neuropathy
- Mild cognitive impairment and dementia
Physical
- A physical examination of patients with the classic form of glycogen-storage disease type IV reveals evidence of liver failure and portal hypertension.
- Patients with other forms of glycogen-storage disease type IV present with symptoms of affected organ or tissue dysfunction. Affected areas include the heart, peripheral muscle, or CNS and peripheral nervous systems.
- Failure to thrive and growth delay may be evident.
- Pallor and pale conjunctiva may be noted in patients with anemia.
- Jaundice may result from hyperbilirubinemia secondary to decreased hepatic excretory function.
- Petechiae and ecchymoses may be observed in patients with thrombocytopenia secondary to splenic sequestration and decreased coagulation factors from hepatic failure.
- Peripheral edema may result from decreased hepatic synthesis of albumin or heart failure.
- The abdomen may protrude. Hepatomegaly is often present, with increased liver span and a firm, nontender liver edge. In addition, ascites, splenomegaly, and a prominent abdominal venous pattern develop in patients with associated portal hypertension.
- Hepatomegaly may be mild or absent in patients with nonprogressive liver disease.
- Evidence of early cardiomyopathy includes the following:
- Decreased peripheral perfusion
- Decreased pulse pressure
- Tachycardia
- Hepatomegaly
- Peripheral edema
- Systolic murmur due to valvular incompetence
- Gallop rhythm
- Abnormal lung auscultatory findings
- Costal and subcostal retractions
- Increased jugular venous pressure
- Periorbital edema in infants
- Patients with glycogen-storage disease type IV that involves the muscles may have muscle atrophy, weakness, and decreased strength.
- Patients with the severe perinatal form of glycogen-storage disease type IV often exhibit severe muscle involvement, including biventricular cardiac dysfunction and facial weakness.2
- Patients with peripheral nerve involvement may exhibit decreased or absent deep tendon reflexes and a peripheral neuropathy with sensory loss, primarily in the lower extremities. At times, the disorder may mimic signs of amyotrophic lateral sclerosis.
- Patients with CNS involvement and leukoencephalopathy may exhibit mild cognitive impairment or dementia.
- An affected fetus or stillborn baby may exhibit arthrogryposis and fetal hydrops.
- Examination of an affected neonate may reveal severe hypotonia; shallow respirations; muscle atrophy; and signs of heart failure such as tachypnea, poor peripheral perfusion, low blood pressure, and periorbital edema.
Causes
- All forms of glycogen-storage disease type IV result from defects in the gene that encodes for the glycogen-branching enzyme (GBE1) located on chromosome band 3p12. The function of this enzyme is to increase the number of branch points during glycogen synthesis. The branched nature of the glycogen molecule is important for its compact nature and solubility within the cell. The absence of this branching activity results in abnormal glycogen with long, unbranched outer chains that resemble amylopectin, which is a glucose polymer that is a major storage polysaccharide in legumes.
- Deficient branching enzyme activity and mutations in the gene that encodes for the glycogen-branching enzyme may be generalized or isolated to a specific cell line or tissue.
- Specific mutations have been identified in patients with classic, perinatal, and nonprogressive hepatic forms of glycogen-storage disease type IV. Further studies to determine genotype-phenotype correlations are in progress.
More on Glycogen-Storage Disease Type IV |
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| Treatment & Medication: Glycogen-Storage Disease Type IV |
| Follow-up: Glycogen-Storage Disease Type IV |
| Multimedia: Glycogen-Storage Disease Type IV |
| References |
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References
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Further Reading
Keywords
glycogen-storage disease type IV, GSD IV, Andersen disease, amylopectinosis, adult polyglucosan body disease, brancher deficiency, familial cirrhosis with deposition of abnormal glycogen, GBE1 deficiency, glycogen-branching enzyme deficiency, type 4 glycogenosis, APBD, glycogen storage disease type IV, hepatosplenomegaly, liver cirrhosis, portal hypertension, esophageal varices, encephalopathy, splenomegaly, ascites, renal dysfunction, pruritus, fatigue, anorexia, peripheral edema, epistaxis, diaphoresis, dyspnea, orthopnea, edema, petechiae, ecchymoses, amyotrophic lateral sclerosis, treatment, diagnosis, end-stage liver failure, liver transplantation
