Genetics of Glycogen-Storage Disease Type IV 

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

Overview

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

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.

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.

 

Presentation

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, 2] Cases of a severe subtype of the perinatal form with fetal akinesia, arthrogryposis, pterygia, and severe skeletal muscle degeneration with onset in the second trimester of pregnancy have been reported.[3]

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 (eg, spastic paraplegia)

  • 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.[4]

Patients with peripheral nerve involvement typically present with neurogenic bladder, spastic paraplegia, or axonal neuropathy.[5] They 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.[6, 7]

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.

A homozygous GBE1 mutation (Tyr329Ser) is the most common finding in Ashkenazi Jewish patients.

 

DDx

 

Workup

Laboratory 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 adult polyglucosan body disease (APBD) and CNS involvement. MRI typically demonstrates medullary and spinal atrophy, mild thinning of corpus callosum, and symmetric periventricular white matter changes with occipital predominance.[5]

Proton MR spectroscopy of the head may reveal changes consistent with white matter degeneration.[8]

Echocardiography may reveal evidence of dilated cardiomyopathy and impaired myocardial function.

Other Tests

Definitive biochemical diagnosis of glycogen-storage disease type IV relies on demonstration of deficient glycogen-branching enzyme activity in the liver or in the muscle tissue.

Because glycogen-storage disease type 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 glycogen-storage disease. Heterozygotes may be identified based on an intermediate reduction in glycogen-branching enzyme activity.

The demonstration of homozygous or compound heterozygous mutations in the GBE1 gene by sequence analysis is considered definitive molecular diagnosis of glycogen-storage disease type IV. Targeted mutation analysis may be considered in Ashkenazi Jewish patients with suspected APBD and when a familial mutation has been previously identified.

Prenatal testing is based on the levels of glycogen-branching enzyme activity in cultured amniocytes and chorionic villi. Histological evaluation of placental biopsy samples for the presence of polyglucosan bodies may provide another method of prenatal diagnosis.[9] Molecular diagnosis may be performed if the parental GBE1 mutations have been identified.

Procedures

Definitive biochemical diagnosis of glycogen-storage disease type 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-fold to 3-fold, with faintly stained basophilic inclusions within their cytoplasm.

Liver section from a patient with glycogen-storage 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.

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. Histological analysis of muscle fibers from affected patients demonstrates severe depletion of myofibrils.[1]

Liver section from a patient with glycogen-storage 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.
 

Treatment

Medical Care

See Consultations for treatment options in glycogen-storage disease type IV (GSD IV).

Surgical Care

In patients with classic glycogen-storage disease type IV, liver transplantation is the most effective treatment.[10, 11, 12] Practice guidelines for the evaluation of the patient for liver transplantation have been established by the American Association for the Study of Liver Diseases.[13]

Immediate complications of liver transplantation include postoperative complications and organ rejection. Because glycogen-storage disease type 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 glycogen-storage disease type 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 glycogen-storage disease type 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

Medication Summary

Medications requirements in glycogen-storage disease type IV (GSD IV) depend on organ system abnormalities.

 

Follow-up

Further Outpatient Care

Perform follow-up in patients with glycogen-storage disease type IV (GSD IV) 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 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.