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Genetics of Glycogen-Storage Disease Type IV

  • Author: Lynne Ierardi-Curto, MD, PhD; Chief Editor: Maria Descartes, MD  more...
 
Updated: Jan 08, 2016
 

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.

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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
  • Renal dysfunction

Hepatic functional capacity also progressively declines, including the following conditions:

  • 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.

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Epidemiology

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.

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Contributor Information and Disclosures
Author

Lynne Ierardi-Curto, MD, PhD Attending Physician, Division of Metabolism, Children's Hospital of Philadelphia

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Edward Kaye, MD Vice President of Clinical Research, Genzyme Corporation

Edward Kaye, MD is a member of the following medical societies: American Academy of Neurology, Society for Inherited Metabolic Disorders, American Society of Gene and Cell Therapy, American Society of Human Genetics, Child Neurology Society

Disclosure: Received salary from Genzyme Corporation for management position.

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Liver section from a patient with glycogen-storage disease type IV (GSD IV) stained with hematoxylin and eosin. Characteristic findings include distorted hepatic architecture with diffuse interstitial fibrosis and wide fibrous septa surrounding micronodular areas of parenchyma. Hepatocytes are typically enlarged 2-fold to 3-fold, with faintly stained basophilic cytoplasmic inclusions.
Liver section from a patient with glycogen-storage disease type IV (GSD IV) stained with periodic acid-Schiff (PAS) after diastase treatment. Coarsely clumped material cytoplasmic material representing the accumulated abnormal glycogen is resistant to diastase treatment and is readily stained with PAS.
 
 
 
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