AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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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. GSD 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 GSD IV.

Progressive liver cirrhosis characterizes the classic form of GSD 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 GSD 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

GSD 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; GSD IV accounts for approximately 3% of all cases.

Mortality/Morbidity

• Classic GSD 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, GSD 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 GSD IV presents in utero or immediately after birth.
• The age of onset in individuals with GSD IV variants that predominantly feature nerve, muscle, or cardiac involvement ranges from early infancy through adulthood.

CLINICAL

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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 GSD IV may include a history of fetal hydrops, cervical cystic hygroma, decreased in utero fetal movements, and severe hypotonia at birth or death in the neonatal period.
• 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 GSD 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, 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 GSD IV reveals evidence of liver failure and portal hypertension.
• Patients with other forms of GSD 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 GSD IV that involves the muscles may have muscle atrophy, weakness, and decreased strength.
• 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 GSD 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 GSD IV. Further studies to determine genotype-phenotype correlations are in progress.

DIFFERENTIALS

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Other Problems to be Considered

Alpha-1 antitrypsin deficiency
Neonatal hepatitis
Respiratory chain defects

WORKUP

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Lab Studies

In patients suspected to have the classic form of glycogen-storage disease type IV (GSD IV), perform laboratory evaluations to assess the degree of liver dysfunction. Patients may exhibit all, some, or none of the associated biochemical abnormalities, depending on the degree of liver dysfunction and counter-regulatory processes.

In general, prolonged prothrombin time (PT) and decreased plasma albumin levels correlate with the degree of hepatic cirrhosis. Increased plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase (GGT) correlate with the degree of hepatocellular insufficiency. Patients with primary muscle, nervous system, or cardiac involvement and minimal or no liver dysfunction may demonstrate laboratory values within reference ranges.

• CBC count: Normochromic anemia or normocytic anemia usually results from chronic blood loss due to coagulopathy, folate deficiency, and hemolysis. Morphologically abnormal erythrocytes on  peripheral blood smear findings result from decreased splenic function. Thrombocytopenia and leukopenia result from splenic sequestration.
• PT, activated partial thromboplastin time, and fibrinogen: Liver disease causes decreased synthesis of vitamin K–dependent coagulation factors and fibrinogen, inadequate absorption of vitamin K, and thrombocytopenia; therefore, progressive liver failure leads to prolonged PT and prolonged activated partial thromboplastin time (aPTT), decreased fibrinogen levels with progressive coagulopathy, and risk of disseminated intravascular coagulation.
• ALT and AST: Measurement of liver enzyme levels usually reveals progressive elevation consistent with hepatocellular damage and release of enzymes into the blood.
• Total and indirect (conjugated) bilirubin: In the early stages of liver dysfunction, conjugated bilirubin levels rise because the liver can conjugate this fluid but cannot adequately excrete it. In patients with progressive liver failure, both conjugated and unconjugated bilirubin levels rise.
• Serum alkaline phosphatase, GGT, and 5' nucleotidase: Levels of these hepatocellular enzymes may be normal or slightly elevated and may vary with the degree of hepatic bile secretory function.
• Serum albumin: Hypoalbuminemia is a result of decreased hepatic synthetic function but also depends on dietary protein intake and on fluid and electrolyte dynamics.
• Electrolytes: Associated renal dysfunction causes electrolyte imbalance with hyponatremia, hypokalemia, and decreased serum calcium and magnesium levels.
• BUN: BUN levels are abnormally low despite associated renal dysfunction, secondary to impaired hepatic synthetic function.
• Creatinine: Creatinine levels are usually within the reference range.
• Serum creatine kinase: Serum creatine kinase levels are within the reference ranges, even in patients with severe hypotonia.
• Blood glucose: Hypoglycemia may result from severe hepatocellular damage and from glycogenolysis and gluconeogenesis that are inadequate to maintain serum glucose.

Imaging Studies

• Abdominal Doppler ultrasonography may reveal the presence of portal hypertension, esophageal varices, and liver echogenicity. Ultrasonography may also reveal portal vein diameter and blood flow directionality.
• Abdominal MRI or CT scanning may reveal evidence of cirrhotic changes in liver parenchyma and the vascular system. Liver and spleen volume quantitation may be performed.
• Characteristic features on liver-spleen scintigraphy using technetium-99m sulfur colloid include decreased uptake in the liver with an irregular pattern and increased uptake in the spleen and bone marrow.
• MRI of the head may reveal leukoencephaly and cortical atrophy in patients with APBD and CNS involvement.
• Echocardiography may reveal evidence of dilated cardiomyopathy and impaired myocardial function.

Other Tests

• Definitive diagnosis of GSD IV relies on demonstration of deficient glycogen-branching enzyme activity in the liver or in the muscle tissue.
• Because GSD IV is a multisystem disorder, evidence of abnormal glycogen content can be demonstrated in many tissues and cells, including the liver, leukocytes, erythrocytes, and cultured skin fibroblasts. The sole exception is APBD in Ashkenazi Jewish patients whose deficient glycogen-branching enzyme activity may be demonstrated only in leukocytes and nerve cells.
• Patients demonstrate approximately 1-10% of the glycogen-branching enzyme activity found in persons without GSD. Heterozygotes may be identified based on an intermediate reduction in glycogen-branching enzyme activity.
• Prenatal testing is based on the levels of glycogen-branching enzyme activity in cultured amniocytes and chorionic villi. Molecular diagnosis may be performed in selected cases.

Procedures

• Definitive diagnosis of GSD IV may require obtaining a biopsy of the liver or other affected organs (eg, muscle, nerve, heart) for microscopic examination and enzyme assay.
• Esophagogastroduodenoscopy is the definitive procedure to document the presence and position of esophageal varices.

Histologic Findings

Characteristic microscopic findings in liver sections include a distorted architecture with diffuse interstitial fibrosis and wide fibrous septa surrounding micronodular areas of parenchyma. Hepatocytes are typically enlarged 2- to 3-fold, with faintly stained basophilic inclusions within their cytoplasm.

Histological analysis of the liver and other affected tissues demonstrates periodic acid-Schiff (PAS)–positive, diastase-resistant, coarsely clumped material consistent with abnormal glycogen. Iodine staining forms a characteristic complex with a distinctive blue color. Electron microscopic examination of affected tissues reveals normal alpha- and beta-glycogen particles in addition to fibrillary aggregates typical of amylopectin. In many reports, the cytoplasm of affected cells contains many of these abnormal aggregates, termed polyglucosan bodies.

TREATMENT

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Medical Care

See Consultations

Surgical Care

• In patients with classic glycogen-storage disease type IV (GSD IV), liver transplantation is the most effective treatment.
  
  
  • Immediate complications of liver transplantation include postoperative complications and organ rejection. Because GSD IV is a multisystem disorder, the long-term success of liver transplantation and its effect on the disease progression in other organs is unclear.
  • Although several patients have reportedly experienced decreased progression and systemic regression after hepatic allografting, presumably due to systemic microchimerism, some patients develop progressive accumulation of abnormal glycogen in other organs after transplantation, ultimately leading to death.

Consultations

• Patients with liver involvement require a pediatric gastroenterologist for initial evaluation and long-term management of liver dysfunction and cirrhosis. The severity of liver dysfunction and complications of portal hypertension determine medical management.
• A patient who presents with clinical symptoms of neuromuscular involvement requires a pediatric neurologist for initial evaluation and management.
• A pediatric cardiologist is recommended for initial evaluation and medical management of the few patients who present with symptoms of cardiac compromise.
• Refer a patient with suspected GSD IV to a metabolic or biochemical genetics specialist for diagnostic evaluation.
• Refer a patient with liver dysfunction to a dietitian experienced with the nutritional support of progressive hepatic failure.
• Refer the family of an affected child to a medical geneticist or genetic counselor to review the inheritance of GSD IV and to discuss prenatal diagnostic testing. Because inheritance is autosomal recessive, parents have a 25% risk of an affected offspring with each pregnancy.

Diet

• If the patient has liver disease, dietary management is necessary to provide adequate nutrient intake to maintain normoglycemia and to improve liver function.
• In patients with classic symptoms who develop progressive liver cirrhosis that necessitates liver transplantation, proper dietary intervention has improved muscle strength and allowed additional time for growth before surgery.

Activity

Do not restrict activity unless the patient experiences acute symptoms of liver failure and complications of cirrhosis.

MEDICATION

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Medications requirements depend on any organ system abnormalities. See Treatment. 

FOLLOW-UP

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Further Outpatient Care

• Perform follow-up to evaluate the progression of liver disease, to determine the need for additional medical and dietary management, and to assess the urgency for surgical intervention. Periodic ultrasonography of the liver to monitor the development of hepatocellular adenoma is suggested.
• Perform periodic follow-up to evaluate progressive organ involvement and failure in patients with predominant nerve, muscle, and cardiac involvement.

Deterrence/Prevention

• The parents of an affected child should be provided genetic counseling regarding the autosomal recessive inheritance pattern and the 1:4 risk (25%) of an affected offspring with each pregnancy.
• The parents of an affected child should be informed that analysis of the GBE1 gene by sequencing and other molecular techniques may identify the mutations in their child. Subsequently, if the mutations of an affected child are identified, then prenatal diagnostic testing may be offered for future pregnancies.
• The parents of an affected child should be informed that if the mutations in an affected child are identified, genetic testing may be offered to close family members to determine carrier status for the GBE1 mutation.

Complications

The following complications may result from the disease process and medical or surgical interventions:

• Patients with liver cirrhosis who develop portal hypertension may develop complications of portosystemic blood shunting, including esophageal varices, encephalopathy splenomegaly, ascites, and renal dysfunction
• Patients with progressive liver disease may develop complications related to declining hepatic functional capacity.
• Patients with cardiomyopathy may die from progressive heart failure despite medical and surgical intervention.
• Patients with nonprogressive liver disease have an increased risk for hepatocellular adenoma and hepatocellular carcinoma.
• Immediate complications of liver transplantation include postoperative complications and organ rejection.
• Long-term complications after liver transplantation include the progression of disease in other organs.

Prognosis

• The prognosis is poor in patients with the perinatal-onset and classic forms who do not undergo liver transplantation. Long-term prognosis for others, including patients with classic glycogen-storage disease type IV (GSD IV) after transplantation, depends on the extent, severity, and progression of this multisystem disorder.

Patient Education

• Educate patients and parents about proper diet management to support liver dysfunction.
• Educate patients and parents about proper evaluation and long-term medical management of complications such as cirrhosis and portal hypertension, heart failure, and neuromuscular dysfunction.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to adequately monitor and manage progressive organ dysfunction and failure
• Failure to adequately discuss the potential benefits and complications of liver transplantation with patients who have classic glycogen-storage disease type IV (GSD IV)
• Failure to discuss the availability of prenatal diagnosis to a couple with a previously affected child
• Failure to consider the diagnosis of GSD IV in a fetus with cervical cystic hygroma and normal chromosome analysis

MULTIMEDIA

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Media file 1:  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- to 3-fold, with faintly stained basophilic cytoplasmic inclusions.
	View Full Size Image
Media type:  Photo

Media file 2:  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.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

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• Akman HO, Karadimas C, Gyftodimou Y. Prenatal diagnosis of glycogen storage disease type IV. Prenat Diagn. Oct 2006;26(10):951-955. [Medline].
• Bao Y, Kishnani P, Wu JY, Chen YT. Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene. J Clin Invest. Feb 15 1996;97(4):941-8. [Medline].
• Brown BI, Brown DH. Branching enzyme activity of cultured amniocytes and chorionic villi: prenatal testing for type IV glycogen storage disease. Am J Hum Genet. Mar 1989;44(3):378-81. [Medline].
• Bruno C, van Diggelen OP, Cassandrini D, et al. Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV). Neurology. Sep 28 2004;63(6):1053-8. [Medline].
• Burrow TA, Hopkin RJ, Bove KE, et al. Non-lethal congenital hypotonia due to glycogen storage disease type IV. Am J Med Genet A. Apr 15 2006;140(8):878-82. [Medline].
• Giuffre B, Parinii R, Rizzuti T, et al. Severe neonatal onset of glycogenosis type IV: clinical and laboratory findings leading to diagnosis in two siblings. J Inherit Metab Dis. 2004;27(5):609-19. [Medline].
• L'hermine-Coulomb A, Beuzen F, Bouvier R, et al. Fetal type IV glycogen storage disease: clinical, enzymatic, and genetic data of a pure muscular form with variable and early antenatal manifestations in the same family. Am J Med Genet A. Dec 1 2005;139(2):118-22. [Medline].
• Lossos A, Meiner Z, Barash V, et al. Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene. Ann Neurol. Dec 1998;44(6):867-72. [Medline].
• McConkie-Rosell A, Wilson C, Piccoli DA, et al. Clinical and laboratory findings in four patients with the non-progressive hepatic form of type IV glycogen storage disease. J Inherit Metab Dis. 1996;19(1):51-8. [Medline].
• Nambu M, Kawabe K, Fukuda T, et al. A neonatal form of glycogen storage disease type IV. Neurology. Aug 12 2003;61(3):392-4. [Medline].
• Nase S, Kunze KP, Sigmund M, et al. A new variant of type IV glycogenosis with primary cardiac manifestation and complete branching enzyme deficiency. In vivo detection by heart muscle biopsy. Eur Heart J. Nov 1995;16(11):1698-704. [Medline].
• Selby R, Starzl TE, Yunis E, et al. Liver transplantation for type I and type IV glycogen storage disease. Eur J Pediatr. 1993;152 Suppl 1:S71-6. [Medline].
• Servidei S, Riepe RE, Langston C, et al. Severe cardiopathy in branching enzyme deficiency. J Pediatr. Jul 1987;111(1):51-6. [Medline].
• Shen J, Liu HM, McConkie-Rosell A, Chen YT. Prenatal diagnosis of glycogen storage disease type IV using PCR-based DNA mutation analysis. Prenat Diagn. Sep 1999;19(9):837-9. [Medline].
• Sokal EM, Van Hoof F, Alberti D, et al. Progressive cardiac failure following orthotopic liver transplantation for type IV glycogenosis. Eur J Pediatr. Mar 1992;151(3):200-3. [Medline].
• Starzl TE, Demetris AJ, Trucco M, et al. Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher's disease. N Engl J Med. Mar 18 1993;328(11):745-9. [Medline].

Article Last Updated: Jul 31, 2007